3-amino-5-phenyl-56-dihydro-2h-[1,4]oxazines

ABSTRACT

The present invention relates to 3-Amino-5-phenyl-5,6-dihydro-2H-[1,4]oxazines of formula I 
     
       
         
         
             
             
         
       
     
     having BACE1 and/or BACE2 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer&#39;s disease and type 2 diabetes.

PRIORITY TO RELATED APPLICATION(S)

This application is a continuation of U.S. application Ser. No.13/460,905, filed May 1, 2012 now pending, which is a continuation ofU.S. application Ser. No. 12/852,538, filed Aug. 9, 2010, now allowed,which claims the benefit of European Patent Application No. 09168132.0,filed Aug. 19, 2009. The entire contents of the above-identifiedapplications are hereby incorporated by reference.

TECHNICAL FIELD

The present invention is concerned with3-Amino-5-phenyl-5,6-dihydro-2H-[1,4]oxazines having BACE1 and/or BACE2inhibitory properties, their manufacture, pharmaceutical compositionscontaining them and their use as therapeutically active substances.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is a neurodegenerative disorder of the centralnervous system and the leading cause of a progressive dementia in theelderly population. Its clinical symptoms are impairment of memory,cognition, temporal and local orientation, judgment and reasoning butalso severe emotional disturbances. There are currently no treatmentsavailable which can prevent the disease or its progression or stablyreverse its clinical symptoms. AD has become a major health problem inall societies with high life expectancies and also a significanteconomic burden for their health systems.

AD is characterized by 2 major pathologies in the central nervous system(CNS), the occurrence of amyloid plaques and neurofibrillar tangles(Hardy et al., The amyloid hypothesis of Alzheimer's disease: progressand problems on the road to therapeutics, Science. 2002 Jul. 19;297(5580):353-6, Selkoe, Cell biology of the amyloid β-protein precursorand the mechanism of Alzheimer's disease, Annu Rev Cell Biol. 1994;10:373-403). Both pathologies are also commonly observed in patientswith Down's syndrome (trisomy 21), which also develop AD-like symptomsin early life. Neurofibrillar tangles are intracellular aggregates ofthe microtubule-associated protein tau (MAPT). Amyloid plaques occur inthe extracellular space; their principal components are Aβ-peptides. Thelatter are a group of proteolytic fragments derived from the β-amyloidprecursor protein (APP) by a series of proteolytic cleavage steps.Several forms of APP have been identified of which the most abundant areproteins of 695, 751 and 770 amino acids length. They all arise from asingle gene through differential splicing. The A/β-peptides are derivedfrom the same domain of the APP but differ at their N- and C-termini,the main species are of 40 and 42 amino-acid length. There are severallines of evidence which strongly suggest that aggregated Aβ-peptides arethe essential molecules in the pathogenesis of AD: 1) amyloid plaquesformed of Aβ-peptides are invariably part of the AD pathology; 2)Aβ-peptides are toxic for neurons; 3) in Familial Alzheimer's Disease(FAD) the mutations in the disease genes APP, PSN1, PSN2 lead toincreased levels of Aβ-peptides and early brain amyloidosis; 4)transgenic mice which express such FAD genes develop a pathology whichbears many resemblances to the human disease. Aβ-peptides are producedfrom APP through the sequential action of 2 proteolytic enzymes termedβ- and γ-secretase. β-Secretase cleaves first in the extracellulardomain of APP approximately 28 amino acids outside of the trans-membranedomain (TM) to produce a C-terminal fragment of APP containing the TM-and the cytoplasmatic domain (CTFβ). CTFβ is the substrate forγ-secretase which cleaves at several adjacent positions within the TM toproduce the Aβ peptides and the cytoplasmic fragment. The γ-secretase isa complex of at least 4 different proteins, its catalytic subunit isvery likely a presenilin protein (PSEN1, PSEN2). The β-secretase (BACE1,Asp2; BACE stands for β-site APP-cleaving enzyme) is an aspartylprotease which is anchored into the membrane by a transmembrane domain(Vassar et al., Beta-secretase cleavage of Alzheimer's amyloid precursorprotein by the transmembrane aspartic protease BACE, Science. 1999 Oct.22; 286(5440):735). It is expressed in many tissues of the humanorganism but its level is especially high in the CNS. Genetic ablationof the BACE1 gene in mice has clearly shown that its activity isessential for the processing of APP which leads to the generation ofAβ-peptides, in the absence of BACE1 no Aβ-peptides are produced (Luo etal., Mice deficient in BACE1, the Alzheimer's beta-secretase, havenormal phenotype and abolished beta-amyloid generation, Nat. Neurosci.2001 March; 4(3):231-2, Roberds et al., BACE knockout mice are healthydespite lacking the primary beta-secretase activity in brain:implications for Alzheimer's disease therapeutics, Hum Mol. Genet. 2001Jun. 1; 10(12):1317-24). Mice which have been genetically engineered toexpress the human APP gene and which form extensive amyloid plaques andAlzheimer's disease like pathologies during aging fail to do so whenβ-secretase activity is reduced by genetic ablation of one of the BACE1alleles (McConlogue et al., Partial reduction of BACE1 has dramaticeffects on Alzheimer plaque and synaptic pathology in APP TransgenicMice. J Biol. Chem. 2007 Sep. 7; 282(36):26326). It is thus presumedthat inhibitors of BACE1 activity can be useful agents for therapeuticintervention in AD.

Type 2 diabetes (T2D) is caused by insulin resistance and inadequateinsulin secretion from pancreatic β-cells leading to poor blood-glucosecontrol and hyperglycemia (M Prentki & CJ Nolan, “Islet beta-cellfailure in type 2 diabetes.” J. Clin. Investig. 2006, 116(7),1802-1812). Patients with T2D have an increased risk of microvascularand macrovascular disease and a range of related complications includingdiabetic nephropathy, retinopathy and cardiovascular disease. In 2000,an estimated 171 million people had the condition with the expectationthat this figure will double by 2030 (S. Wild, G. Roglic, A. Green, R.Sicree & H. King, “Global prevalence of diabetes”, Diabetes Care 2004,27(5), 1047-1053), making the disease a major healthcare problem. Therise in prevalence of T2D is associated with an increasingly sedentarylifestyle and high-energy food intake of the world's population (PZimmet, KGMM Alberti & J Shaw, “Global and societal implications of thediabetes epidemic” Nature 2001, 414, 782-787).

β-Cell failure and consequent dramatic decline in insulin secretion andhyperglycemia marks the onset of T2D. Most current treatments do notprevent the loss of β-cell mass characterizing overt T2D. However,recent developments with GLP-1 analogues, gastrin and other agents showthat preservation and proliferation of β-cells is possible to achieve,leading to an improved glucose tolerance and slower progression to overtT2D (LL Baggio & DJ Drucker, “Therapeutic approaches to preserve isletmass in type 2 diabetes”, Annu. Rev. Med. 2006, 57, 265-281).

Tmem27 has been identified as a protein promoting beta-cellproliferation (P Akpinar, S Kuwajima, J Krützfeldt, M Stoffel, “Tmem27:A cleaved and shed plasma membrane protein that stimulates pancreatic βcell proliferation”, Cell Metab. 2005, 2, 385-397) and insulin secretion(K Fukui, Q Yang, Y Cao, N Takahashi et al., “The HNF-1 targetCollectrin controls insulin exocytosis by SNARE complex formation”, CellMetab. 2005, 2, 373-384). Tmem27 is a 42 kDa membrane glycoprotein whichis constitutively shed from the surface of β-cells, resulting from adegradation of the full-length cellular Tmem27. Overexpression of Tmem27in a transgenic mouse increases β-cell mass and improves glucosetolerance in a diet-induced obesity (DIO) model of diabetes.Furthermore, siRNA knockout of Tmem27 in a rodent β-cell proliferationassay (e.g. using INS1e cells) reduces the proliferation rate,indicating a role for Tmem27 in control of β-cell mass.

In the same proliferation assay, BACE2 inhibitors also increaseproliferation. However, BACE2 inhibition combined with Tmem27 siRNAknockdown results in low proliferation rates. Therefore, it is concludedthat BACE2 is the protease responsible for the degradation of Tmem27.Furthermore, in vitro, BACE2 cleaves a peptide based on the sequence ofTmem27. The closely related protease BACE1 does not cleave this peptideand selective inhibition of BACE1 alone does not enhance proliferationof β-cells.

The close homolog BACE2 is a membrane-bound aspartyl protease and isco-localized with Tmem27 in human pancreatic β-cells (G Finzi, F Franzi,C Placidi, F Acquati et al., “BACE2 is stored in secretory granules ofmouse and rat pancreatic beta cells”, Ultrastruct Pathol. 2008, 32(6),246-251). It is also known to be capable of degrading APP (1Hussain, DPowell, D Howlett, G Chapman et al., “ASP 1 (BACE2) cleaves the amyloidprecursor protein at the β-secretase site” Mol Cell Neurosci. 2000, 16,609-619), IL-1R2 (P Kuhn, E Marjaux, A Imhof, B De Strooper et al.,“Regulated intramembrane proteolysis of the interleukin-1 receptor II byalpha-, beta-, and gamma-secretase” J. Biol. Chem. 2007, 282(16),11982-11995) and ACE2. The capability to degrade ACE2 indicates apossible role of BACE2 in the control of hypertension.

Inhibition of BACE2 is therefore proposed as a treatment for T2D withthe potential to preserve and restore β-cell mass and stimulate insulinsecretion in pre-diabetic and diabetic patients. It is therefore anobject of the present invention to provide selective BACE2 inhibitors.Such compounds are useful as therapeutically active substances,particularly in the treatment and/or prevention of diseases which areassociated with the inhibition of BACE2.

Furthermore, the formation, or formation and deposition, of β-amyloidpeptides in, on or around neurological tissue (e.g., the brain) areinhibited by the present compounds, i.e. inhibition of the Aβ-productionfrom APP or an APP fragment.

Inhibitors of BACE1 and/or BACE2 can in addition be used to treat thefollowing diseases:

IBM (inclusion body myositis) (Vattemi G. et al., Lancet. 2001 Dec. 8;358(9297):1962-4), Down's Syndrome (Barbiero L. et al, Exp Neurol. 2003August; 182(2):335-45), Wilson's Disease (Sugimoto I. et al., J Biol.Chem. 2007 Nov. 30; 282(48):34896-903), Whipple's disease (Desnues B. etal., Clin Vaccine Immunol. 2006 February; 13(2):170-8), SpinoCerebellarAtaxia 1 and SpinoCerebellar Ataxia 7 (Gatchel J. R. et al., Proc NatlAcad Sci USA 2008 Jan. 29; 105(4):1291-6), Dermatomyositis (Greenberg S.A. et al., Ann Neurol. 2005 May; 57(5):664-78 and Greenberg S. A. etal., Neurol 2005 May; 57(5):664-78), Kaposi Sarcoma (Lagos D. et al,Blood, 2007 Feb. 15; 109(4):1550-8), Glioblastoma multiforme(E-MEXP-2576,http://www.ebi.ac.uk/microarray-as/aer/result?queryFor=PhysicalArrayDesign&aAccession=A-MEXP-258),Rheumatoid arthritis (Ungethuem U. et al, GSE2053), Amyotrophic lateralsclerosis (Koistinen H. et al., Muscle Nerve. 2006 October; 34(4):444-50and Li Q. X. et al, Aging Cell. 2006 April; 5(2):153-65), Huntington'sDisease (Kim Y. J. et al., Neurobiol Dis. 2006 May; 22(2):346-56. Epub2006 Jan. 19 and Hodges A. et al., Hum Mol. Genet. 2006 Mar. 15;15(6):965-77. Epub 2006 Feb. 8), Multiple Mieloma (Kihara Y. et al, ProcNatl Acad Sci U S A. 2009 Dec. 22; 106(51):21807-12), Malignant melanoma(Talantov D. et al, Clin Cancer Res. 2005 Oct. 15; 11(20):7234-42),Sjogren syndrome (Basset C. et al., Scand J. Immunol. 2000 March;51(3):307-11), Lupus erythematosus (Grewal P. K. et al, Mol Cell Biol.2006, July; 26(13):4970-81), Macrophagic myofasciitis, juvenileidiopathic arthritis, granulomatous arthritis, Breast cancer (Hedlund M.et al, Cancer Res. 2008 Jan. 15; 68(2):388-94 and Kondoh K. et al.,Breast Cancer Res Treat. 2003 March; 78(1):37-44), Gastrointestinaldiseases (Hoffmeister A. et al, JOP. 2009 Sep. 4; 10(5):501-6),Autoimmune/inflammatory diseases (Woodard-Grice A. V. et al., J Biol.Chem. 2008 Sep. 26; 283(39):26364-73. Epub 2008 Jul. 23), RheumatoidArthritis (Toegel S. et al, Osteoarthritis Cartilage. 2010 February;18(2):240-8. Epub 2009 Sep. 22), Inflammatory reactions (LichtenthalerS. F. et al., J Biol. Chem. 2003 Dec. 5; 278(49):48713-9. Epub 2003 Sep.24), Arterial Thrombosis (Merten M. et al., Z Kardiol. 2004 November;93(11):855-63), Cardiovascular diseases such as Myocardial infarctionand stroke (Maugeri N. et al., Srp Arh Celok Lek. 2010 January; 138Suppl 1:50-2) and Graves disease (Kiljański J. et al, Thyroid. 2005July; 15(7): 645-52).

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I,

wherein the substituents and variables are as described below, andpharmaceutically acceptable salts thereof.

The present invention also provides pharmaceutical compositionscontaining a compound of formula I or a pharmaceutically acceptable saltthereof. The invention also provides methods for the manufacture of thecompounds and compositions of the invention. Further, the inventionprovides methods for the control or prevention of illnesses such asAlzheimer's disease and type 2 diabetes. Furthermore, the formation, orformation and deposition, of β-amyloid plaques in, on or aroundneurological tissue (e.g., the brain) are inhibited by the presentcompounds by inhibiting the Aβ production from APP or an APP fragment.

The present compounds have Asp2 (β-secretase, BACE1 or Memapsin-2)inhibitory activity and can therefore be used in the therapeutic and/orprophylactic treatment of diseases and disorders that exhibit elevatedβ-amyloid levels and/or β-amyloid oligomers and/or β-amyloid plaques andfurther deposits, particularly Alzheimer's disease. The presentcompounds have BACE2 inhibitory activity and can therefore be used inthe therapeutic and/or prophylactic treatment of diseases and disorderssuch as type 2 diabetes and other metabolic disorders.

Furthermore the use of compounds of formula I in the treatment ofamyotrophic lateral sclerosis (ALS), arterial thrombosis,autoimmune/inflammatory diseases, cancer such as breast cancer,cardiovascular diseases such as myocardial infarction and stroke,dermatomyositis, Down's Syndrome, gastrointestinal diseases,Glioblastoma multiforme, Graves Disease, Huntington's Disease, inclusionbody myositis (IBM), inflammatory reactions, Kaposi Sarcoma, KostmannDisease, lupus erythematosus, macrophagic myofasciitis, juvenileidiopathic arthritis, granulomatous arthritis, malignant melanoma,multiple myeloma, rheumatoid arthritis, Sjogren syndrome,SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7, Whipple's Diseaseand Wilson's Disease.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I andpharmaceutically acceptable salts thereof, the preparation of suchcompounds, medicaments, i.e. pharmaceutical compositions, containingthem and their manufacture. The invention also provides methods for thetherapeutic and/or prophylactic treatment of diseases and disorders thatare associated by inhibition of BACE1 and/or BACE2 activity, such asAlzheimer's disease and type 2 diabetes, by administering a compound ofthe invention. The invention also provides methods for the therapeuticand/or prophylactic treatment of diseases such as amyotrophic lateralsclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases,cancer such as breast cancer, cardiovascular diseases such as myocardialinfarction and stroke, dermatomyositis, Down's Syndrome,gastrointestinal diseases, Glioblastoma multiforme, Graves Disease,Huntington's Disease, inclusion body myositis (IBM), inflammatoryreactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus,macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatousarthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis,Sjogren syndrome, SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7,Whipple's Disease and Wilson's Disease.

The following definitions of the general terms used in the presentdescription apply irrespectively of whether the terms in question appearalone or in combination with other groups.

The term “lower alkyl”, alone or in combination with other groups,stands for a hydrocarbon radical which can be linear or branched, withsingle or multiple branching, whereby the alkyl group in generalcomprises 1 to 6 carbon atoms, for example, methyl (Me), ethyl (Et),propyl, isopropyl (i-propyl), n-butyl, i-butyl (iso-butyl), 2-butyl(sec-butyl), t-butyl (tert-butyl) and the like. Preferred alkyl groupsare groups with 1 to 4 carbon atoms, for example methyl, ethyl andisopropyl. Most preferred is methyl.

The phrase “lower alkyl substituted by”, alone or in combination withother groups, refers to lower alkyl as defined above, which issubstituted by one or multiple substituents, preferably 1-5substituents, individually selected from the group of substituentsconsisting of acetamidyl, acetyl, amido, amino, carboxy, cyano,cycloalkyl, halogen, halogen-lower alkoxy, heterocyclyl, hydroxy, (loweralkyl,H)N—, (lower alkyl,lower alkyl)N—, lower alkyl-S(O)₂—, loweralkoxy, nitro and the like. Preferred “lower alkyl substituted by” arelower alkyl substituted by 1-5 substituents individually selected fromcycloalkyl, halogen, halogen-lower alkoxy and lower alkoxy. Morepreferred are trifluoro-lower alkyl, halogen-methyl and halogen-ethyl.More preferred are trifluoro-methyl, trifluoro-ethyl andpentafluoro-ethyl. Most preferred are methoxy-methyl,3,3,3-trifluoro-1-(tetrahydro-furan-2-yl-propyl,1,1,2,2,2-pentafluoro-ethyl, 1,1,2,2-tetrafluoro-ethyl.,1,1,1,2-tetrafluoro-ethyl, 2,2,2-trifluoroethyl, 2,2-difluoro-ethyl,2-fluoro-ethyl, difluoro-methyl and fluoro-isopropyl.

The term “halogen-lower alkyl”, alone or in combination with othergroups, refers to lower alkyl, which is substituted by one or multiplehalogens. Preferred are trifluoro-lower alkyl, halogen-methyl andhalogen-ethyl. More preferred “halogen-lower alkyl” is trifluoro-methyl,trifluoro-ethyl and pentafluoro-ethyl. Most preferred are1,1,2,2,2-pentafluoro-ethyl, 1,1,2,2-tetrafluoro-ethyl.,1,1,1,2-tetrafluoro-ethyl, 2,2,2-trifluoroethyl, 2,2-difluoro-ethyl,2-fluoro-ethyl, difluoro-methyl and fluoro-isopropyl.

The term “lower alkoxy-lower alkyl”, alone or in combination with othergroups, refers to lower alkyl, which is substituted by one or multiplelower alkoxy as defined here within. Examples are MeO-Me(methoxy-methyl, H₃C—O—CH₂—), 1MeO-Et, 2MeO-Et, 1MeO-2EtO-propyl and thelike. Preferred is MeO-Me.

The term “cyano-lower alkyl”, alone or in combination with other groups,refers to lower alkyl, which is substituted by one or multiple cyano asdefined here within. Examples are NC-Me (cyano-methyl, H₃C—O—CH₂—,1NC-Et, 2NC-propyl, and the like.

The term “cyano”, alone or in combination with other groups, refers toN≡C— (NC—).

The term “halogen”, alone or in combination with other groups, denoteschloro (Cl), iodo (I), fluoro (F) and bromo (Br). Preferred “halogen” ischloro and fluoro. Most preferred is fluoro.

The term “aryl”, alone or in combination with other groups, refers to anaromatic carbocyclic group comprising 6 to 14, preferably 6 to 10,carbon atoms and having at least one aromatic ring or multiple condensedrings in which at least one ring is aromatic. Examples of “aryl” includebenzyl, biphenyl, indanyl, naphthyl, phenyl (Ph) and the like. Preferred“aryl” are phenyl and benzyl. Most preferred is phenyl.

The phrase “aryl substituted by”, alone or in combination with othergroups, refers to an aryl group which is substituted by one or multiplesubstituents, preferably 1-4 substituents, whereby substitution at eachring atom individually substituted with a substituent individuallyselected from the group consisting of amino, amino-lower alkyl, carboxy,carboxy-lower alkyl, lower alkyl-N(lower alkyl)-CO—, NH₂—CO—, loweralkyl-NH—CO—, cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy,halogen-lower alkyl, hydroxy, hydroxy-lower alkyl, lower alkoxy, loweralkoxy-lower alkyl, lower alkyl, lower alkyl-CO—, lower alkyl-COO-loweralkyl, (lower alkyl,H)N—, (lower alkyl,lower alkyl)N—, loweralkyl-S(O)₂—, N(lower alkyl,H)-lower alkyl, N(lower alkyl,loweralkyl)-lower alkyl, nitro and the like. Preferred “aryl substituted by”are aryl substituted by 1-4 substituents individually selected fromcyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-loweralkyl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl. Morepreferred are halogens, most preferred are F, Cl and I. Also preferredare halogen-aryl, halogen-phenyl, fluoro-phenyl, fluoro-aryl,chloro-phenyl, chloro-aryl, fluoro-chloro-aryl and fluoro-chloro-phenyl,iodo-chloro-aryl and iodo-chloro-phenyl. Most preferred are2,4-dichloro-phenyl, 2,5-difluoro-phenyl, 3-chloro-phenyl,4-chloro-2-fluoro-phenyl, 4-chloro-2-iodo-phenyl, 4-chloro-phenyl,4-cyano-2-fluoro-phenyl and 4-oxazol-5-yl-phenyl.

The term “heteroaryl”, alone or in combination with other groups, refersto an aromatic carbocyclic group of having a single 5 to 8 membered ringor multiple condensed rings comprising 6 to 14, more preferably 6 to 10,ring atoms and containing 1, 2 or 3 heteroatoms, in which group at leastone heterocyclic ring is aromatic and the heteroatoms are individuallyselected from O, S and N. Examples of “heteroaryl” include benzofuryl,benzoimidazolyl, benzooxazinyl, benzothiazinyl, benzothiazolyl,benzothienyl, benzotriazolyl, furyl, imidazolyl, indazolyl, indolyl,isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl(pyrazyl), pyrazolo[1,5-a]pyridinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl,triazolyl and the like. Preferred heteroaryls are furyl, indazolyl,oxazolyl, pyrazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolyl, pyridinyl,thiazolyl and thienyl. Most preferred are 1H-indazol-3-yl,1H-pyrazol-3-yl, fur-3-yl, isoxazol-3-yl, oxazol-2-yl, oxazol-4-yl,pyrazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl, pyridin-2-yl, pyrimidin-2-yl,pyrimidin-4-yl, thiazol-4-yl, thiazol-5-yl, thien-2-yl, thien-3-yl andthiophen-2-yl.

The phrase “heteroaryl substituted by”, alone or in combination withother groups, refers to a heteroaryl which is substituted by one ormultiple substituents, preferably 1-4 substituents, whereby substitutionat each ring atom individually is selected from the group consisting ofamino, amino-lower alkyl, carboxy, carboxy-lower alkyl, loweralkyl-N(lower alkyl)-CO—, NH₂—CO—, lower alkyl-NH—CO—, cyano,cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl,hydroxy, hydroxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl,lower alkyl, lower alkyl-CO—, lower alkyl-COO-lower alkyl, (loweralkyl,H)N—, (lower alkyl, lower alkyl)N—, lower alkyl-S(O)₂—, N(loweralkyl,H)-lower alkyl, N(lower alkyl,lower alkyl)-lower alkyl, nitro andthe like. Preferred substituents are halogen, lower alkyl, halogen-loweralkyl and halogen-lower alkoxy, most preferred are methyl, dimethyl,trifluoro-methyl, trifluoro-ethyl, trifluoro-ethoxy, chloro, dichloroand difluoro. Preferred “heteroaryl substituted by” are heteroarylsubstituted by 1-4 substituents individually selected from cyano,cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl,lower alkoxy, lower alkoxy-lower alkyl and lower alkyl. More preferredare lower alkyl-heteroaryl, halogen-lower alkyl-heteroaryl,halogen-lower alkoxy-heteroaryl, halogen-pyridinyl, halogen-thienyl,lower alkyl-thienyl, lower alkyl-thiazolyl, lower alkyl-oxazolyl, loweralkyl-furyl, halogen-lower alkyl-pyrazolyl, lower alkyl-indazolyl,halogen-lower alkoxy-pyridinyl and halogen-halogen-loweralkyl-pyridinyl. Most preferred are 5-phenyl-oxazol-4-yl,5-cyano-pyridin-2-yl, 5-chloro-pyridin-2-yl, 3,5-dichloro-pyridin-2-yl,3,5-difluoro-pyridin-2-yl, 5-chloro-thien-2-yl, 5-chloro-pyrimidin-2-yl,3-fluoro-pyridin-2-yl, 3-chloro-thiophen-2-yl,5-chloro-3-fluoro-pyridin-2-yl, 5-fluoro-pyridin-2-yl,5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl,3-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl,5-(2-fluoro-ethoxy)-pyridin-2-yl, 5-(2,2-difluoro-ethoxy)-pyridin-2-yl,5-difluoromethoxy-pyridin-2-yl,1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl,5-trifluoromethyl-pyrazin-2-yl, 5-trifluoromethyl-pyrimidin-2-yl,5-cyclopropylmethoxy-pyridin-2-yl, 5-but-3-enyloxy-pyridin-2-yl,5-benzyloxy-pyridin-2-yl, 5-furan-2-yl-isoxazole-3-yl,5-furan-2-yl-pyridin-2-yl, 5-thiophen-2-yl-isoxazole-3-yl,5-pyrrolidin-1-yl-pyridin-2-yl, 2,5-dimethyl-fur-3-yl,2,5-dimethyl-oxazol-4-yl, 2,5-dimethyl-thien-3-yl,5-methyl-pyrazine-2-yl, 1-methyl-1H-indazol-3-yl, 2-methyl-oxazol-4-yl,2-methyl-thiazol-4-yl, 5-butyl-pyridin-2-yl,1,1-difluoromethyl-1H-pyrazol-3-yl, 3,5-difluoro-pyridin-2-yl,3-chloro-5-trifluoromethyl-pyridin-2-yl,4-chloro-1-methyl-1H-pyrazole-3-yl, 5-chloro-3-ethyl-pyridin-2-yl,3-sec-butyl-5-chloro-pyridin-2-yl, 5-chloro-3-methyl-pyridin-2-yl,3-chloro-5-cyano-pyridin-2-yl and2-methyl-4-trifluoromethyl-thiazol-5-yl.

The term “cycloalkyl”, alone or in combination with other groups, refersto a 3 to 6 membered carbon ring, for example cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. Preferred cycloalkyl are cyclopropyl andcyclobutyl. Most preferred is cyclopropyl.

The phrase “cycloalkyl substituted by”, alone or in combination withother groups, refers to a cycloalkyl group which is substituted by oneor multiple substituents, preferably 1-4 substituents, wherebysubstitution at each ring atom individually is selected from the groupconsisting of amino, amino-lower alkyl, carboxy, carboxy-lower alkyl,lower alkyl-N(lower alkyl,H)—CO—, lower alkyl-N(lower alkyl,loweralkyl)-CO—, lower alkyl-NH₂—CO—, cyano, cyano-lower alkyl, halogen,halogen-lower alkoxy, halogen-lower alkyl, hydroxy, hydroxy-lower alkyl,lower alkoxy, lower alkoxy-lower alkyl, lower alkyl, lower alkyl-CO—,lower alkyl-COO-lower alkyl, (lower alkyl,H)N—, (lower alkyl,loweralkyl)N—, lower alkyl-S(O)₂—, N(lower alkyl,H)-lower alkyl, N(loweralkyl,lower alkyl)-lower alkyl, nitro and the like. Preferred“cycloalkyl substituted by” are cycloalkyl substituted by 1-4substituents individually selected from cyano, cyano-lower alkyl,halogen, halogen-lower alkoxy, halogen-lower alkyl, lower alkoxy, loweralkoxy-lower alkyl and lower alkyl. Preferred are, lower alkoxy-loweralkyl, halogen and halogen-lower alkyl. Most preferred are2,2-difluoro-cycloprop-1-yl, 3-chloro-cyclobut-1-yl,3,3-difluoro-cyclobut-1-yl, 1-trifluoromethyl-cycloprop-1-yl and1-methoxymethyl-cycloprop-1-yl.

The term “lower alkoxy”, alone or in combination with other groups,stands for an —O-lower alkyl radical which can be linear or branched,with single or multiple branching, whereby the alkyl group in generalcomprises 1 to 6 carbon atoms, for example, methoxy (OMe, MeO), ethoxy(OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, i-butoxy (iso-butoxy),2-butoxy (sec-butoxy), t-butoxy (tert-butoxy), isopentyloxy(i-pentyloxy) and the like. Preferred “lower alkoxy” are groups with 1to 4 carbon atoms. Most preferred are ethoxy and methoxy.

The term “halogen-lower alkoxy”, alone or in combination with othergroups, refers to lower alkoxy, which is substituted by one or multiplehalogens. Preferred “halogen-lower alkoxy” are fluoro-lower alkoxy,fluoro-ethoxy and halogen-ethoxy.

The term “heterocyclyl”, alone or in combination with other groups,refers to a 4 to 8 membered ring containing 1, 2 or 3 ring heteroatomsindividually selected from N, O or S. 1 or 2 ring heteroatoms arepreferred. Preferred are 4 to 6 membered “heterocyclyl”, more preferred5 to 6 membered “heterocyclyl”, each containing 1 or 2 ring heteroatomsselected from N, O or S. Examples of “heterocyclyl” include azepanyl,azetidyl, diazepanyl, morpholinyl, oxazepanyl, oxazolidyl, oxetanyl,piperazinyl, piperidyl, pyrrolidinyl, tetrahydrofuryl,tetrahydropyridyl, tetrahydropyryl, tetrahydrothienyl, thiazolidyl,thiomorpholinyl and the like. Preferred is tetrahydro-furan-3-yl.

The phrase “heterocyclyl substituted by”, alone or in combination withother groups, refers to a heterocyclyl which is substituted by one ormultiple substituents, preferably 1-4 substituents, whereby substitutionat each ring atom individually is selected from the group consisting ofamino, amino-lower alkyl, carboxy, carboxy-lower alkyl, loweralkyl-N(lower alkyl,H)—CO—, lower alkyl-N(lower alkyl,lower alkyl)-CO—,lower alkyl-NH₂—CO—, cyano, cyano-lower alkyl, halogen, halogen-loweralkoxy, halogen-lower alkyl, hydroxy, hydroxy-lower alkyl, lower alkoxy,lower alkoxy-lower alkyl, lower alkyl, lower alkyl-CO—, loweralkyl-COO-lower alkyl, (lower alkyl,H)N—, (lower alkyl,lower alkyl)N—,lower alkyl-S(O)₂—, N(lower alkyl,H)-lower alkyl, N(lower alkyl,loweralkyl)-lower alkyl, nitro and the like. Preferred “heterocyclylsubstituted by” are heterocyclyl substituted by 1-4 substituentsindividually selected from cyano, cyano-lower alkyl, halogen,halogen-lower alkoxy, halogen-lower alkyl, lower alkoxy, loweralkoxy-lower alkyl and lower alkyl.

The term “pharmaceutically acceptable salts” refers to salts that aresuitable for use in contact with the tissues of humans and animals.Examples of suitable salts with inorganic and organic acids are, but arenot limited to acetic acid, citric acid, formic acid, fumaric acid,hydrochloric acid, lactic acid, maleic acid, malic acid,methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonicacid, succinic acid, sulfuric acid, sulphuric acid, tartaric acid,trifluoroacetic acid and the like. Preferred are formic acid andhydrochloric acid. Most preferred is hydrochloric acid.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The terms “pharmaceutically acceptable carrier” and “pharmaceuticallyacceptable auxiliary substance” refer to carriers and auxiliarysubstances such as diluents or excipients that are compatible with theother ingredients of the formulation.

Substituents at a double bond or a ring can be present in cis (═Z—) ortrans (=E-) form, unless the stereochemistry is explicitly depicted inthe corresponding compound formula I.

The term “pharmaceutical composition” encompasses a product comprisingspecified ingredients in pre-determined amounts or proportions, as wellas any product that results, directly or indirectly, from combiningspecified ingredients in specified amounts. Preferably it encompasses aproduct comprising one or more active ingredients, and an optionalcarrier comprising inert ingredients, as well as any product thatresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

The following table lists abbreviations used within the presentdocument.

TABLE 1 abbreviations HPLC high performance liquid chromatographyHuenig's base N,N-diisopropylethylamine Lawesson's reagent2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4- diphosphetane-2,4-disulfide NMRnuclear magnetic resonance tert-butyl-x-phos2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl

The invention also provides pharmaceutical compositions, methods ofusing, and methods of preparing the aforementioned compounds.

All separate embodiments can be combined.

One embodiment of the invention is a compound of formula I,

wherein

X is O or S,

R¹ is selected from the group consisting of

-   -   i) lower alkyl,    -   ii) lower alkyl substituted by 1-5 substituents individually        selected from cycloalkyl, halogen, halogen-lower alkoxy and        lower alkoxy, and    -   iii) cycloalkyl,        R² is selected from the group consisting of    -   i) H,    -   ii) lower alkyl,    -   iii) lower alkyl substituted by 1-5 substituents individually        selected from cycloalkyl, halogen, halogen-lower alkoxy,        heterocyclyl and lower alkoxy,    -   iv) aryl,    -   v) aryl substituted by 1-4 substituents individually selected        from cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy,        halogen-lower alkyl, heteroaryl, lower alkoxy, lower        alkoxy-lower alkyl and lower alkyl,    -   vi) cycloalkyl,    -   vii) cycloalkyl substituted by 1-4 substituents individually        selected from cyano, cyano-lower alkyl, halogen, halogen-lower        alkoxy, halogen-lower alkyl, lower alkoxy, lower alkoxy-lower        alkyl and lower alkyl,    -   viii) heteroaryl,    -   ix) heteroaryl substituted by 1-4 substituents individually        selected from aryl, cyano, cyano-lower alkyl, halogen,        halogen-lower alkoxy, halogen-lower alkyl, cycloalkyl-lower        alkoxy, lower alkenyl-lower alkoxy, aryl-lower alkoxy,        heteroaryl, heterocyclyl, lower alkoxy, lower alkoxy-lower alkyl        and lower alkyl,    -   x) heterocyclyl, and    -   xi) heterocyclyl, substituted by 1-4 substituents individually        selected from amino, cyano, cyano-lower alkyl, halogen,        halogen-lower alkoxy, halogen-lower alkyl, lower alkoxy, lower        alkoxy-lower alkyl and lower alkyl,        R³ is individually selected from the group consisting of    -   i) halogen and    -   ii) lower alkyl,        R⁴ is individually selected from the group consisting of    -   i) H and    -   ii) lower alkyl,        R⁵ is individually selected from the group consisting of    -   i) H and    -   ii) lower alkyl,        R⁶ is individually selected from the group consisting of    -   i) H and    -   ii) lower alkyl,        R⁷ is individually selected from the group consisting of    -   i) H,    -   ii) aryl, and    -   iii) lower alkyl, and        n is 0, 1 or 2,        or pharmaceutically acceptable salts thereof.

One embodiment of the invention is a compound of formula I, wherein

X is O or S,

R¹ is selected from the group consisting of

-   -   i) lower alkyl and    -   ii) cycloalkyl,        R² is selected from the group consisting of    -   i) H,    -   ii) lower alkyl substituted by 1-5 substituents individually        selected from cycloalkyl, halogen, heterocyclyl and lower        alkoxy,    -   iii) aryl substituted by 1-4 substituents individually selected        from cyano, halogen and heteroaryl,    -   iv) cycloalkyl,    -   v) cycloalkyl substituted by 1-4 substituents individually        selected from halogen, halogen-lower alkyl, lower alkoxy-lower        alkyl and lower alkyl,    -   vi) heteroaryl,    -   vii) heteroaryl substituted by 1-4 substituents individually        selected from aryl, cyano, halogen, halogen-lower alkoxy,        halogen-lower alkyl, cycloalkyl-lower alkoxy, lower        alkenyl-lower alkoxy, aryl-lower alkoxy, heteroaryl,        heterocyclyl, and lower alkyl, and    -   viii) heterocyclyl,        R³ is halogen,        R⁴ is H or lower alkyl,        R⁵ is H or lower alkyl,        R⁶ is H or lower alkyl,        R⁷ is H, aryl or lower alkyl, and        n is 0 or 1.

One embodiment of the invention is a compound of formula I, which is acompound of formula Ix,

wherein

X is O or S,

R¹ is selected from the group consisting of

-   -   i) lower alkyl,    -   ii) lower alkyl substituted by 1-5 substituents individually        selected from cycloalkyl, halogen, halogen-lower alkoxy and        lower alkoxy,    -   iii) cycloalkyl, and        R² is selected from the group consisting of    -   i) lower alkyl substituted by 1-5 halogen,    -   ii) aryl,    -   iii) aryl substituted by 1-4 substituents individually selected        from cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy,        halogen-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl and        lower alkyl,    -   iv) heteroaryl, and    -   v) heteroaryl substituted by 1-4 substituents individually        selected from cyano, cyano-lower alkyl, halogen, halogen-lower        alkoxy, halogen-lower alkyl, lower alkoxy, lower alkoxy-lower        alkyl and lower alkyl,        R³ is individually selected from the group consisting of    -   i) halogen and    -   ii) lower alkyl, and        n is 0, 1 or 2,        or pharmaceutically acceptable salts thereof.

One embodiment of the invention is a compound of formula Ix, wherein

X is O or S,

R¹ is selected from the group consisting of

-   -   i) lower alkyl,    -   ii) lower alkyl substituted by 1-5 substituents individually        selected from cycloalkyl, halogen, halogen-lower alkoxy and        lower alkoxy,    -   iii) cycloalkyl, and        R² is selected from the group consisting of    -   i) lower alkyl substituted by 1-5 halogen,    -   ii) aryl,    -   iii) aryl substituted by 1-4 substituents individually selected        from cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy,        halogen-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl and        lower alkyl,    -   iv) cycloalkyl,    -   v) cycloalkyl substituted by 1-4 substituents individually        selected from cyano, cyano-lower alkyl, halogen, halogen-lower        alkoxy, halogen-lower alkyl, lower alkoxy, lower alkoxy-lower        alkyl and lower alkyl,    -   vi) heteroaryl,    -   vii) heteroaryl substituted by 1-4 substituents individually        selected from cyano, cyano-lower alkyl, halogen, halogen-lower        alkoxy, halogen-lower alkyl, lower alkoxy, lower alkoxy-lower        alkyl and lower alkyl,    -   viii) heterocyclyl, and    -   ix) heterocyclyl, substituted by 1-4 substituents individually        selected from cyano, cyano-lower alkyl, halogen, halogen-lower        alkoxy, halogen-lower alkyl, lower alkoxy, lower alkoxy-lower        alkyl and lower alkyl,        R³ is individually selected from the group consisting of    -   i) halogen and    -   ii) lower alkyl, and        n is 0, 1 or 2,        or pharmaceutically acceptable salts thereof.

One embodiment of the invention is a compound of formula Ix, wherein

X is O or S,

R¹ is lower alkyl or cycloalkyl,R² is selected from the group consisting of

-   -   i) lower alkyl substituted by 1-5 halogen,    -   ii) aryl,    -   iii) aryl substituted by 1-4 halogen,    -   iv) heteroaryl, and    -   v) heteroaryl substituted by 1-4 substituents individually        selected from halogen, halogen-lower alkoxy, halogen-lower alkyl        and lower alkyl,        R³ is halogen, and        n is 0 or 1,        or pharmaceutically acceptable salts thereof.

One embodiment of the invention is a compound of formula I or Ix, whereX is O, R¹ is methyl, R² is pyridinyl or pyridinyl substituted by 1 or 2halogens, selected independently from fluoro and chloro, R³ is fluoroand n is 1.

One embodiment of the invention is a compound of formula I or Ix, whereX is O, R¹ is methyl, R² is pyridinyl or pyridinyl substituted by 1 or 2halogens, selected independently from fluoro and chloro and n is 0.

One embodiment of the invention is a compound of formula I or Ix, whereX is O, R¹ is methyl, R² is phenyl or phenyl substituted by 1 or 2halogens, selected independently from fluoro and chloro, R³ is fluoroand n is 1.

One embodiment of the invention is a compound of formula I or Ix, whereX is O, R¹ is methyl, R² is phenyl or phenyl substituted by 1 or 2halogens, selected independently from fluoro and chloro and n is 0.

One embodiment of the invention is a compound of formula I or Ix, whereX is O.

One embodiment of the invention is a compound of formula I or Ix, whereX is S.

One embodiment of the invention is a compound of formula I or Ix, whereR¹ is selected from the group consisting of lower alkyl and cycloalkyl.

One embodiment of the invention is a compound of formula I or Ix, whereR¹ is selected from the group consisting of methyl and cyclopropyl.

One embodiment of the invention is a compound of formula I or Ix, whereR¹ is lower alkyl.

One embodiment of the invention is a compound of formula I or Ix, whereR¹ is methyl.

One embodiment of the invention is a compound of formula I or Ix, whereR¹ is cycloalkyl.

One embodiment of the invention is a compound of formula I or Ix, whereR¹ is cyclopropyl.

One embodiment of the invention is a compound of formula I or Ix, whereR² is selected from the group consisting of

-   i) H,-   ii) lower alkyl substituted by 1-5 substituents individually    selected from cycloalkyl, halogen, heterocyclyl and lower alkoxy,-   iii) aryl substituted by 1-4 substituents individually selected from    cyano, halogen and heteroaryl,-   iv) cycloalkyl,-   v) cycloalkyl substituted by 1-4 substituents individually selected    from halogen, halogen-lower alkyl and lower alkoxy-lower alkyl,-   vi) heteroaryl,-   vii) heteroaryl substituted by 1-4 substituents individually    selected from aryl, cyano, halogen, halogen-lower alkoxy,    halogen-lower alkyl, cycloalkyl-lower alkoxy, lower alkenyl-lower    alkoxy, aryl-lower alkoxy, heteroaryl, heterocyclyl, and lower    alkyl, and-   vi) heterocyclyl.

One embodiment of the invention is a compound of formula I or Ix, whereR² is lower alkyl substituted by 1-5 halogens, aryl substituted by 1-4halogens, heteroaryl or heteroaryl substituted by 1-4 substituentsindividually selected from halogen, halogen-lower alkoxy, halogen-loweralkyl and lower alkyl.

One embodiment of the invention is a compound of formula I or Ix, whereR² is heteroaryl substituted by 1-4 substituents individually selectedfrom halogen, halogen-lower alkoxy, halogen-lower alkyl and lower alkyl.

One embodiment of the invention is a compound of formula I or Ix, whereR² is 1-methyl-1H-indazol-3-yl, 2-methyl-oxazol-4-yl,2-methyl-thiazol-4-yl, 3-chloro-phenyl, 4-chloro-2-fluoro-phenyl,4-chloro-2-iodo-phenyl, 4-chloro-phenyl, 5-chloro-pyridin-2-yl,5-chloro-thien-2-yl, 1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl,1,1,2,2,2-pentafluoro-ethyl, 5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl,pyrazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl, 2,4-dichloro-phenyl,2,5-difluoro-phenyl, 2,5-dimethyl-fur-3-yl, 2,5-dimethyl-oxazol-4-yl,2,5-dimethyl-thien-3-yl, 3,5-dichloro-pyridin-2-yl,3,5-difluoro-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix, whereR² is 1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl,1,1,1,2-tetrafluoro-ethyl, 1,1,2,2,2-pentafluoro-ethyl,1,1,2,2-tetrafluoro-ethyl, 1,1-difluoromethyl-1H-pyrazole-3-yl,1-methoxymethyl-cycloprop-1-yl, 1-methyl-1H-indazol-3-yl,1-trifluoromethyl-cycloprop-1-yl, 2,2,2-trifluoroethyl-,2,2-difluoro-cycloprop-1-yl, 2,2-difluoro-ethyl, 2,4-dichloro-phenyl,2,5-difluoro-phenyl, 2,5-dimethyl-fur-3-yl, 2,5-dimethyl-oxazol-4-yl,2,5-dimethyl-thien-3-yl, 2-fluoro-ethyl,2-methyl-4-trifluoromethyl-thiazole-5-yl, 2-methyl-oxazol-4-yl,2-methyl-thiazol-4-yl, 3-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl,3,3,3-trifluoro-1-(tetrahydro-furan-2-yl)-propyl,3,3-difluoro-cyclobut-1-yl, 3,5-dichloro-pyridin-2-yl,3,5-difluoro-pyridin-2-yl, 3-chloro-5-cyano-pyridin-2-yl,3-chloro-5-trifluoromethyl-pyridin-2-yl, 3-chloro-cyclobut-1-yl,3-chloro-phenyl, 3-chloro-thiophen-2-yl, 3-fluoro-pyridin-2-yl,3-methyl-thiophen-2-yl, 3-sec-butyl-5-chloro-pyridin-2-yl,4-chloro-1-methyl-1H-pyrazole-3-yl, 4-chloro-2-fluoro-phenyl,4-chloro-2-iodo-phenyl, 4-chloro-phenyl, 4-cyano-2-fluoro-phenyl,4-oxazol-5-yl-phenyl, 5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl,5-(2,2-difluoro-ethoxy)-pyridin-2-yl, 5-(2-fluoro-ethoxy)-pyridin-2-yl,5-benzyloxy-pyridin-2-yl, 5-but-3-enyloxy-pyridin-2-yl,5-butyl-pyridin-2-yl, 5-chloro-3-ethyl-pyridin-2-yl,5-chloro-3-fluoro-pyridin-2-yl, 5-chloro-3-methyl-pyridin-2-yl,5-chloro-pyridin-2-yl, 5-chloro-pyrimidin-2-yl, 5-chloro-thien-2-yl,5-cyano-pyridin-2-yl, 5-cyclopropylmethoxy-pyridin-2-yl,5-difluoromethoxy-pyridin-2-yl, 5-fluoro-pyridin-2-yl,5-furan-2-yl-isoxazol-3-yl, 5-furan-2-yl-pyridin-2-yl,5-methyl-pyrazin-2-yl, 5-phenyl-oxazol-4-yl,5-pyrrolidin-1-yl-pyridin-2-yl, 5-thiophen-2-yl-isoxazol-3-yl,5-trifluoromethyl-pyrazin-2-yl, 5-trifluoromethyl-pyrimidin-2-yl,cyclopropyl, difluoro-methyl, ethyl, fluoro-isopropyl, H, isopropyl,methyl, methoxy-methyl, oxazole-2-yl, pyrazin-2-yl,pyrazolo[1,5-a]pyridin-2-yl, pyrimidin-4-yl or tetrahydro-furan-3-yl.

One embodiment of the invention is a compound of formula I or Ix, whereR² is 1-methyl-1H-indazol-3-yl, 2-methyl-oxazol-4-yl,2-methyl-thiazol-4-yl, 3-chloro-phenyl, 4-chloro-2-fluoro-phenyl,4-chloro-2-iodo-phenyl, 4-chloro-phenyl, 5-chloro-pyridin-2-yl,5-chloro-thien-2-yl, 1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl,1,1,2,2,2-pentafluoro-ethyl, 5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl,pyrazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl, 2,4-dichloro-phenyl,2,5-difluoro-phenyl, 2,5-dimethyl-fur-3-yl, 2,5-dimethyl-oxazol-4-yl,2,5-dimethyl-thien-3-yl, 3,5-dichloro-pyridin-2-yl or3,5-difluoro-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix, whereR² is 1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl,1,1,1,2-tetrafluoro-ethyl, 1,1,2,2,2-pentafluoro-ethyl,1,1,2,2-tetrafluoro-ethyl, 1,1-difluoromethyl-1H-pyrazole-3-yl,1-methoxymethyl-cycloprop-1-yl, 1-methyl-1H-indazol-3-yl,1-trifluoromethyl-cycloprop-1-yl, 2,2,2-trifluoroethyl-,2,2-difluoro-cycloprop-1-yl, 2,2-difluoro-ethyl, 2,4-dichloro-phenyl,2,5-difluoro-phenyl, 2,5-dimethyl-fur-3-yl, 2,5-dimethyl-oxazol-4-yl,2,5-dimethyl-thien-3-yl, 2-fluoro-ethyl,2-methyl-4-trifluoromethyl-thiazole-5-yl, 2-methyl-oxazol-4-yl,2-methyl-thiazol-4-yl, 3-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl,3,3,3-trifluoro-1-(tetrahydro-furan-2-yl-propyl,3,3-difluoro-cyclobut-1-yl, 3,5-dichloro-pyridin-2-yl,3,5-difluoro-pyridin-2-yl, 3-chloro-5-cyano-pyridin-2-yl,3-chloro-5-trifluoromethyl-pyridin-2-yl, 3-chloro-cyclobut-1-yl,3-chloro-phenyl, 3-chloro-thiophen-2-yl, 3-fluoro-pyridin-2-yl,3-methyl-thiophen-2-yl, 3-sec-butyl-5-chloro-pyridin-2-yl,4-chloro-1-methyl-1H-pyrazol-3-yl, 4-chloro-2-fluoro-phenyl,4-chloro-2-iodo-phenyl, 4-chloro-phenyl, 4-chloro-phenyl,4-cyano-2-fluoro-phenyl, 4-oxazol-5-yl-phenyl,5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl,5-(2,2-difluoro-ethoxy)-pyridin-2-yl, 5-(2-fluoro-ethoxy)-pyridin-2-yl,5-benzyloxy-pyridin-2-yl, 5-but-3-enyloxy-pyridin-2-yl,5-butyl-pyridin-2-yl, 5-chloro-3-ethyl-pyridin-2-yl,5-chloro-3-fluoro-pyridin-2-yl, 5-chloro-3-methyl-pyridin-2-yl,5-chloro-pyridin-2-yl, 5-chloro-pyrimidin-2-yl, 5-chloro-thien-2-yl,5-cyano-pyridin-2-yl, 5-cyclopropylmethoxy-pyridin-2-yl,5-difluoromethoxy-pyridin-2-yl, 5-fluoro-pyridin-2-yl,5-furan-2-yl-isoxazole-3-yl, 5-furan-2-yl-pyridin-2-yl,5-methyl-pyrazine-2-yl, 5-phenyl-oxazole-4-yl,5-pyrrolidin-1-yl-pyridin-2-yl or 5-thiophen-2-yl-isoxazole-3-yl.

One embodiment of the invention is a compound of formula I or Ix, whereR² is H.

One embodiment of the invention is a compound of formula I or Ix whereR² is lower alkyl.

One embodiment of the invention is a compound of formula I or Ix, whereR² is methyl.

One embodiment of the invention is a compound of formula I or Ix, whereR² is ethyl.

One embodiment of the invention is a compound of formula I or Ix, whereR² is isopropyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is lower alkyl substituted by 1-5 halogens.

One embodiment of the invention is a compound of formula I or Ix whereR² is 1,1,2,2,2-pentafluoro-ethyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 1,1,2,2-tetrafluoro-ethyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 1,1,1,2-tetrafluoro-ethyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 2,2,2-trifluoroethyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 2,2-difluoro-ethyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 2-fluoro-ethyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is difluoro-methyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is fluoro-isopropyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is lower alkyl substituted by lower alkoxy.

One embodiment of the invention is a compound of formula I or Ix whereR² is methoxy-methyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is lower alkyl substituted by halogen and heterocyclyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3,3,3-trifluoro-1-(tetrahydro-furan-2-yl-propyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is cycloalkyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is cyclopropyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is cycloalkyl substituted by halogen.

One embodiment of the invention is a compound of formula I or Ix whereR² is 2,2-difluoro-cycloprop-1-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3-chloro-cyclobut-1-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3,3-difluoro-cyclobut-1-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is cycloalkyl substituted by halogen-lower alkyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 1-trifluoromethyl-cycloprop-1-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is cycloalkyl substituted by lower alkoxy-lower alkyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 1-methoxymethyl-cycloprop-1-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is aryl substituted by 1-4 halogens.

One embodiment of the invention is a compound of formula I or Ix whereR² is phenyl substituted by 1-4 halogens.

One embodiment of the invention is a compound of formula I or Ix whereR² is 2,4-dichloro-phenyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 2,5-difluoro-phenyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3-chloro-phenyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 4-chloro-2-fluoro-phenyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 4-chloro-2-iodo-phenyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 4-chloro-phenyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is aryl substituted by halogen and cyano.

One embodiment of the invention is a compound of formula I or Ix whereR²4-cyano-2-fluoro-phenyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is aryl substituted by heteroaryl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 4-oxazol-5-yl-phenyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is aryl substituted by 1-4 substituents individually selected fromhalogen, halogen-lower alkoxy, halogen-lower alkyl and lower alkyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl.

One embodiment of the invention is a compound of formula I or Ix whereR² is pyrazin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is pyrazolo[1,5-a]pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is pyrimidin-4-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is oxazole-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by aryl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-phenyl-oxazol-4-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by cyano.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-cyano-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by halogen.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-chloro-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3,5-dichloro-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3,5-difluoro-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-chloro-thien-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-chloro-pyrimidin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3-fluoro-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3-chloro-thiophen-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-chloro-3-fluoro-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-fluoro-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by halogen-lower alkoxy.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-(2-fluoro-ethoxy)-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-(2,2-difluoro-ethoxy)-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-difluoromethoxy-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by halogen-lower alkyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-trifluoromethyl-pyrazin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-trifluoromethyl-pyrimidin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by cycloalkyl-lower alkoxy.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-cyclopropylmethoxy-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by lower alkenyl-lower alkoxy.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-but-3-enyloxy-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by aryl-lower alkoxy.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-benzyloxy-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by heteroaryl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-furan-2-yl-isoxazole-3-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-furan-2-yl-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-thiophen-2-yl-isoxazole-3-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by heterocyclyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-pyrrolidin-1-yl-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by lower alkyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 2,5-dimethyl-fur-3-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 2,5-dimethyl-oxazol-4-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 2,5-dimethyl-thien-3-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-methyl-pyrazine-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 1-methyl-1H-indazol-3-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 2-methyl-oxazol-4-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 2-methyl-thiazol-4-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-butyl-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 1,1-difluoromethyl-1H-pyrazol-3-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3,5-difluoro-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3-methyl-thiophen-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by halogen and lower alkyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3-chloro-5-trifluoromethyl-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 4-chloro-1-methyl-1H-pyrazole-3-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-chloro-3-ethyl-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3-sec-butyl-5-chloro-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 5-chloro-3-methyl-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by halogen and cyano.

One embodiment of the invention is a compound of formula I or Ix whereR² is 3-chloro-5-cyano-pyridin-2-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heteroaryl substituted by halogen-lower alkyl and lower alkyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is 2-methyl-4-trifluoromethyl-thiazol-5-yl.

One embodiment of the invention is a compound of formula I or Ix whereR² is heterocyclyl.

One embodiment of the invention is a compound of formula I or Ix whereR² is tetrahydro-furan-3-yl.

One embodiment of the invention is a compound of formula I or Ix where nis 0.

One embodiment of the invention is a compound of formula I or Ix where nis 1.

One embodiment of the invention is a compound of formula I or Ix whereR³ is halogen.

One embodiment of the invention is a compound of formula I or Ix whereR³ is F.

One embodiment of the invention is a compound of formula I or Ixselected from the group consisting of

-   3,5-Difluoro-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   3,5-Dichloro-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   (RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-chloro-2-fluoro-benzamide,-   (RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,4-dichloro-benzamide,-   (RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,5-difluoro-benzamide,-   (RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-3-chloro-benzamide,-   5-Chloro-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   5-Chloro-thiophene-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   2,5-Dimethyl-thiophene-3-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   2-Methyl-thiazole-4-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   2,5-Dimethyl-oxazole-4-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   2-Methyl-oxazole-4-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   2,5-Dimethyl-furan-3-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   1-(2,2,2-Trifluoro-ethyl)-1H-pyrazole-3-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   1-Methyl-1H-indazole-3-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   Pyrazolo[1,5-a]pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   (RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-chloro-2-iodo-benzamide,-   5-Chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   (RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-benzamide,-   5-Chloro-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Chloro-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,-   Pyrazine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   (RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2,2,3,3,3-pentafluoro-propionamide,-   (RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-thiobenzamide,-   5-Chloro-pyridine-2-carboxylic acid [3-((3R,6R) and    (3S,6S)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-Chloro-pyridine-2-carboxylic acid [3-((3R,6S)— and    (3S,6R)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-Chloro-pyridine-2-carboxylic acid    [3-((3R,6R)-5-amino-3-methyl-6-phenyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-Chloro-pyridine-2-carboxylic acid    [3-((3R,6S)-5-amino-3-methyl-6-phenyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-Butyl-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   3,5-Dichloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-Chloro-pyrimidine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Trifluoromethyl-furan-3-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   3-Fluoro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   2-Methyl-oxazole-4-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   1-Difluoromethyl-1H-pyrazole-3-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   3,5-Difluoro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-cyano-2-fluoro-benzamide,-   4-Chloro-1-methyl-1H-pyrazole-3-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   3-Methyl-thiophene-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Phenyl-oxazole-4-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   3-Chloro-thiophene-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   2-Methyl-4-trifluoromethyl-thiazole-5-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   3-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid    [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3,6,6-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   (RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-oxazol-5-yl-benzamide,-   (RS)-2,2-Difluoro-cyclopropanecarboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   Cyclopropanecarboxylic acid    [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   1-Trifluoromethyl-cyclopropanecarboxylic acid    [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   (RS)-2,2-Difluoro-cyclopropanecarboxylic acid    [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   1-Trifluoromethyl-cyclopropanecarboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   3-Chloro-cyclobutanecarboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   3,3-Difluoro-cyclobutanecarboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-Cyclopropylmethoxy-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   5-(2-Fluoro-ethoxy)-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   5-(2,2-Difluoro-ethoxy)-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   Pyrimidine-4-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   5-But-3-enyloxy-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   5-Methyl-pyrazine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   5-Benzyloxy-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   3-Chloro-5-cyano-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Chloro-3-fluoro-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   5-Cyano-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Chloro-3-ethyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   3 (RS)-sec-Butyl-5-chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Cyano-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Difluoromethoxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Chloro-3-fluoro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Furan-2-yl-isoxazole-3-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Furan-2-yl-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Pyrrolidin-1-yl-pyridine-2-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Thiophen-2-yl-isoxazole-3-carboxylic acid    [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-O-4-fluoro-phenyl-]-amide,-   (RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-3,3,3-trifluoro-propionamide,-   Oxazole-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Trifluoromethyl-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Trifluoromethyl-pyrimidine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2,2,3,3-tetrafluoro-propionamide,-   N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2-methoxy-acetamide,-   (RS)—N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-3,3,3-trifluoro-2-[(RS)-1-(tetrahydro-furan-2-yl)methyl]-propionamide,-   1-Methoxymethyl-cyclopropanecarboxylic acid the    1-methoxymethyl-cyclopropanecarboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   (RS)—N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2-fluoro-propionamide,-   N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-isobutyramide,-   (RS)—N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2-fluoro-propionamide,-   N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2,2-difluoro-propionamide,-   N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2,2-difluoro-acetamide,-   (R)—N-(3-(5-Amino-3-methyl-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-2-fluoro-2-methylpropanamide,-   N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-acetamide,-   N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-propionamide,-   N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-3-methyl-butyramide,-   (RS)-Tetrahydro-furan-3-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   N-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-formamide,-   5-Chloro-3-methyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,    and-   5-Fluoro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,    or pharmaceutically acceptable salts thereof.

One embodiment of the invention is a compound of formula I or Ixselected from the group consisting of

-   5-Chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-Chloro-pyridine-2-carboxylic acid [3-((3R,6R) and    (3S,6S)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-Chloro-pyridine-2-carboxylic acid [3-((3R,6S)— and    (3S,6R)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   3,5-Dichloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   1-Difluoromethyl-1H-pyrazole-3-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   1-Difluoromethyl-1H-pyrazole-3-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-Chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid    [3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3,6,6-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   3-Chloro-5-cyano-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Cyano-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-Difluoromethoxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,    and-   5-Chloro-3-fluoro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,    or pharmaceutically acceptable salts thereof.

One embodiment of the invention is a compound of formula I or Ixselected from the group consisting of

-   1-(2,2,2-Trifluoro-ethyl)-1H-pyrazole-3-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   1-Methyl-1H-indazole-3-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   2,5-Dimethyl-furan-3-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   2,5-Dimethyl-oxazole-4-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   2,5-Dimethyl-thiophene-3-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   2-Methyl-oxazole-4-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   2-Methyl-thiazole-4-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   3,5-Dichloro-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   3,5-Difluoro-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid    [3-(5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide    hydrochloride,-   5-Chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   5-Chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,-   5-Chloro-thiophene-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,-   N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2,2,3,3,3-pentafluoro-propionamide,-   N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-thiobenzamide,-   N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-chloro-2-fluoro-benzamide,-   N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,4-dichloro-benzamide,-   N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,5-difluoro-benzamide,-   N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-3-chloro-benzamide,-   N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl-phenyl]-4-chloro-2-iodo-benzamide,-   N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-benzamide,-   Pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide    hydrochloride and-   Pyrazolo[1,5-a]pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,    or pharmaceutically acceptable salts thereof.

One embodiment of the invention is a compound of formula I or Ixselected from the group consisting of 5-Chloro-pyridine-2-carboxylicacid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideand 5-Chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl-4-fluoro-phenyl]-amide,or pharmaceutically acceptable salts thereof.

One embodiment of the invention is a process for preparing a compound offormula Ix as defined in the embodiments, which process comprisesamination of a compound of formula XXII,

to a compound of formula I′, which compound of formula I′ can optionallyfurther react with a thiation agent to the corresponding compound offormula I″

wherein R¹, R², R³ are as defined in the embodiments and A is loweralkoxy.

One embodiment of the invention is a compound of formula Ix, wheneverprepared by a process as defined above.

One embodiment of the invention is a compound of formula Ix, obtainableby a process as defined above.

One embodiment of the invention is a compound of formula I or Ix asdefined in any of the embodiments, for use as therapeutically activesubstance.

One embodiment of the invention is a compound of formula I or Ix asdefined in any of the embodiments, for the use as inhibitor of BACE1and/or BACE2 activity.

One embodiment of the invention is a compound of formula I or Ix asdefined in any of the embodiments, for the use in inhibition of BACE1activity.

One embodiment of the invention is a compound of formula I or Ix asdefined in any of the embodiments, for the use in inhibition of BACE2activity.

One embodiment of the invention is a compound of formula I or Ix asdefined in any of the embodiments, for the use in inhibition of BACE1and BACE2 activity.

One embodiment of the invention is a compound of formula I or Ix asdefined in any of the embodiments, for the use in inhibition of BACE1 orBACE2 activity.

One embodiment of the invention is a compound of formula I or Ix asdefined in any of the embodiments, for the use as therapeutically activesubstance for the therapeutic and/or prophylactic treatment of diseasesand disorders characterized by elevated β-amyloid levels and/orβ-amyloid oligomers and/or β-amyloid plaques and further deposits,particularly Alzheimer's disease.

One embodiment of the invention is a compound of formula I or Ix asdefined in any of the embodiments, for the use as therapeutically activesubstance for the therapeutic and/or prophylactic treatment ofAlzheimer's disease.

One embodiment of the invention is a compound of formula I or Ix asdefined in any of the embodiments, for the use as therapeutically activesubstance for the therapeutic and/or prophylactic treatment of diabetes,particularly type 2 diabetes.

One embodiment of the invention is a compound of formula I or Ix asdefined in any of the embodiments, for the use as therapeutically activesubstance for the therapeutic and/or prophylactic treatment of type 2diabetes.

One embodiment of the invention is a compound of formula I or Ix asdefined in any of the embodiments, for the use as therapeutically activesubstance for the therapeutic and/or prophylactic treatment ofamyotrophic lateral sclerosis (ALS), arterial thrombosis,autoimmune/inflammatory diseases, cancer such as breast cancer,cardiovascular diseases such as myocardial infarction and stroke,dermatomyositis, Down's Syndrome, gastrointestinal diseases,Glioblastoma multiforme, Graves' Disease, Huntington's Disease,inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma,Kostmann Disease, lupus erythematosus, macrophagic myofasciitis,juvenile idiopathic arthritis, granulomatous arthritis, malignantmelanoma, multiple myeloma, rheumatoid arthritis, Sjogren syndrome,SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7, Whipple's Disease orWilson's Disease.

One embodiment of the invention is a pharmaceutical compositioncomprising a compound as defined in any of the embodiments as an activeingredient and a pharmaceutically acceptable carrier and/or apharmaceutically acceptable auxiliary substance.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the manufacture of a medicament for thetherapeutic and/or prophylactic treatment of diseases and disorderscharacterized by elevated β-amyloid levels and/or β-amyloid oligomersand/or β-amyloid plaques and further deposits, particularly Alzheimer'sdisease.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the manufacture of a medicament for thetherapeutic and/or prophylactic treatment of Alzheimer's disease.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the manufacture of a medicament for thetherapeutic and/or prophylactic treatment of diabetes, particularly type2 diabetes.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the manufacture of a medicament for thetherapeutic and/or prophylactic treatment of type 2 diabetes.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the manufacture of a medicament for thetherapeutic and/or prophylactic treatment of amyotrophic lateralsclerosis (ALS), arterial thrombosis, autoimmune/inflammatory diseases,cancer such as breast cancer, cardiovascular diseases such as myocardialinfarction and stroke, dermatomyositis, Down's Syndrome,gastrointestinal diseases, Glioblastoma multiforme, Graves' Disease,Huntington's Disease, inclusion body myositis (IBM), inflammatoryreactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus,macrophagic myofasciitis, juvenile idiopathic arthritis, granulomatousarthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis,Sjogren syndrome, SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7,Whipple's Disease or Wilson's Disease.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the use in inhibition of BACE1 and/or BACE2activity.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the use in inhibition of BACE1 activity.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the use in inhibition of BACE2 activity.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the use in inhibition of BACE1 and BACE2activity.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the use in inhibition of BACE1 or BACE2activity.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the therapeutic and/or prophylactic treatmentof diseases and disorders characterized by elevated β-amyloid levelsand/or β-amyloid oligomers and/or β-amyloid plaques and furtherdeposits, particularly Alzheimer's disease.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the therapeutic and/or prophylactic treatmentof Alzheimer's disease.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the therapeutic and/or prophylactic treatmentof diabetes, particularly type 2 diabetes.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the therapeutic and/or prophylactic treatmentof type 2 diabetes.

One embodiment of the invention is the use of a compound as defined inany of the embodiments for the therapeutic and/or prophylactic treatmentof amyotrophic lateral sclerosis (ALS), arterial thrombosis,autoimmune/inflammatory diseases, cancer such as breast cancer,cardiovascular diseases such as myocardial infarction and stroke,dermatomyositis, Down's Syndrome, gastrointestinal diseases,Glioblastoma multiforme, Graves' Disease, Huntington's Disease,inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma,Kostmann Disease, lupus erythematosus, macrophagic myofasciitis,juvenile idiopathic arthritis, granulomatous arthritis, malignantmelanoma, multiple myeloma, rheumatoid arthritis, Sjogren syndrome,SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7, Whipple's Disease orWilson's Disease.

One embodiment of the invention is a method for the use in inhibition ofBACE1 and/or BACE2 activity, which method comprises administering acompound as defined in any of the embodiments to a human being oranimal.

One embodiment of the invention is a method for the use in inhibition ofBACE1 activity, which method comprises administering a compound asdefined in any of the embodiments to a human being or animal.

One embodiment of the invention is a method for the use in inhibition ofBACE2 activity, which method comprises administering a compound asdefined in any of the embodiments to a human being or animal.

One embodiment of the invention is a method for the use in inhibition ofBACE1 and BACE2 activity, which method comprises administering acompound as defined in any of the embodiments to a human being oranimal.

One embodiment of the invention is a method for the use in inhibition ofBACE1 or BACE2 activity, which method comprises administering a compoundas defined in any of the embodiments to a human being or animal.

One embodiment of the invention is a method for the use in inhibition ofBACE1 and/or BACE2 activity, particularly for the therapeutic and/orprophylactic treatment of diseases and disorders characterized byelevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloidplaques and further deposits, Alzheimer's disease, diabetes or type 2diabetes, which method comprises administering a compound of formula Iaccording to any of the embodiments to a human being or animal.

One embodiment of the invention is a method for the use in inhibition ofBACE1 and/or BACE2 activity, particularly for the therapeutic and/orprophylactic treatment of amyotrophic lateral sclerosis (ALS), arterialthrombosis, autoimmune/inflammatory diseases, cancer such as breastcancer, cardiovascular diseases such as myocardial infarction andstroke, dermatomyositis, Down's Syndrome, gastrointestinal diseases,Glioblastoma multiforme, Graves' Disease, Huntington's Disease,inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma,Kostmann Disease, lupus erythematosus, macrophagic myofasciitis,juvenile idiopathic arthritis, granulomatous arthritis, malignantmelanoma, multiple myeloma, rheumatoid arthritis, Sjogren syndrome,SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7, Whipple's Disease orWilson's Disease.

Furthermore, the invention includes all optical isomers, i.e.diastereoisomers, diastereomeric mixtures, racemic mixtures, all theircorresponding enantiomers and/or tautomers as well as their solvates.

The compounds of formula I can contain one or more asymmetric centersand can therefore occur as racemates, racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers.Additional asymmetric centers can be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centerwill independently produce two optical isomers and it is intended thatall of the possible optical isomers and diastereomers in mixtures and aspure or partially purified compounds are included within this invention.The present invention is meant to encompass all such isomeric forms ofthese compounds. The independent syntheses of these diastereomers ortheir chromatographic separations can be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry can be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds can be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Preferredexamples of isomers of a compound of formula I is a compound of formulaIa, Ib, Ic or Id, wherein the residues have the meaning as described inthe embodiments. Preferred are compounds of formula Ib or Id.

In the embodiments, where optically pure enantiomers are provided,optically pure enantiomer means that the compound contains >90% of thedesired isomer by weight, preferably >95% of the desired isomer byweight, or more preferably >99% of the desired isomer by weight, saidweight percent based upon the total weight of the isomer(s) of thecompound. Chirally pure or chirally enriched compounds can be preparedby chirally selective synthesis or by separation of enantiomers. Theseparation of enantiomers can be carried out on the final product oralternatively on a suitable intermediate.

A compound of formula I can also be present in its respective tautomericform.

The compounds of formula I can be prepared in accordance with thefollowing schemes. The starting material is commercially available orcan be prepared in accordance with known methods. Any previously definedresidues and variables will continue to have the previously definedmeaning unless otherwise indicated.

The compounds of formula I can be prepared through a number of syntheticroutes for example as illustrated in schemes 1-4. The preparation ofcompounds of formula I of the present invention can be carried out insequential or convergent synthetic routes. Syntheses of the compounds ofthe invention are shown in the following schemes 1-4. The skillsrequired for carrying out the reaction and purification of the resultingproducts are known to those skilled in the art. The substituents andindices used in the following description of the processes have thesignificance given herein before unless indicated to the contrary.

In more detail, the compounds of formula I can be manufactured by themethods given below, by the methods given in the examples or byanalogous methods. Appropriate reaction conditions for the individualreaction steps are known to a person skilled in the art. The reactionsequence is not limited to the one displayed in schemes described below,however, depending on the starting materials and their respectivereactivity the sequence of reaction steps can be freely altered.Starting materials are either commercially available or can be preparedby methods analogous to the methods given below, by methods described inreferences cited in the description or in the examples, or by methodsknown in the art.

The compounds of formula I described in the schemes 1-4 can be isolatedand purified by methods known to those skilled in the art, such as butnot limited to ion exchange chromatography, solid phase extraction,liquid-liquid extraction, silica chromatography, crystallization andpreparative HPLC.

According to scheme 1, ketones of general formula IV (wherein Y has themeaning of a leaving group like halogen, e.g. bromide) can be reactedwith cyanides, like potassium cyanide, together with ammonium carbonatein polar solvents such as alcohols, e.g. ethanol, water ortetrahydrofuran and mixtures thereof, to form hydantoins of formula V.The hydantoin can then be treated with water along with a base such assodium hydroxide or a strong acid such as sulfuric acid at temperaturesranging from ambient temperature to reflux to yield the amino acid offormula VI. The amino alcohol of formula VIII is obtained byesterification of the acid of formula VI with a lower alcohol, such asmethanol or ethanol, followed by reduction of the resulting amino esterof formula VII with lithium aluminum hydride or other suitable reagentsboth steps performed under conditions known to those skilled in the art.N-Acylation of the aminoalcohol of formula VIII can be effected bycondensation with halogenated acetic acid derivatives, such aschloroacetic acid using condensation reagents like benzotriazolederivatives, e.g.O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate(HBTU) and the like in inert solvents, or with acid chloride derivativessuch as chloroacetyl chloride in presence of a base such astriethylamine in an inert solvent both methods under conditions known tothose skilled in the art and yielding acetyl derivatives of formula IX.Lactams of formula X can be prepared by cyclization of the alcohol offormula IX with base, such as potassium tert-butylate, in solvents suchas tert-butanol at temperatures ranging from room temperature to reflux.The iminoether of formula XI can be synthesized by treatment of thelactam of formula X with alkyl oxonium salts, e.g. trimethyloxoniumtetrafluoroborate or triethyloxonium tetrafluoroborate. Noncommercialketones of general formula IV can be synthesized by routes such asdepicted in scheme 1 or by other routes known to those skilled in theart. Weinreb amides of formula III can be obtained by standardcondensation reactions of the acids of formula II withN,O-dimethylhydroxylamine or by the intermediate formation of the acylchloride of acids of formula II using an agent such as oxalyl chlorideor thionyl chloride using standard conditions such astriethylamine/dichloromethane. The amides of formula III can be reactedwith organometallics such as methylmagnesium chloride in inert aproticsolvents such as tetrahydrofuran or diethyl ether to yield the desiredketones of formula IV.

For the further transformation to the aniline derivative of formulaXIII, Pd(0)-catalyzed amination reactions of aryl halides can be appliedwherein as ammonia equivalents lithium bis(trimethylsilyl)amide,triphenylsilylamine, or benzophenone imine are used as described in theart (Organic Letters, 2001, 3(21), 3417-3419 or Bioorganic & MedicinalChemistry Letters 14 (2004), 6011-6016). In scheme 2, the reactionleading to the benzophenone imine derivative of formula XII isexemplified as well as its cleavage under acidic conditions to yield theaniline derivative XIII.

The synthesis of amides of formula XIV can be performed by standardprocedures, such as e.g. by reaction with activated acyl derivatives,e.g. acyl halides or anhydrides, or by condensation reactions of theacid using as condensation reagent carbodiimides, e.g.1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or benzotriazolederivatives, e.g.O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate(HBTU) and the like.

The iminoether of formula XV can be obtained by treatment of the lactamof formula XIV with alkyl oxonium salts, e.g. trimethyloxoniumtetrafluoroborate or triethyloxonium tetrafluoroborate.

Treatment of the iminoether of formula XV with ammonium salt such asammonium chloride in polar solvents like alcohols, e.g. methanol yieldsthe final compound of formula I′.

Alternatively, compounds of formula I′ can be obtained as follows:According to scheme 3, the formation of a methyltriphenyl-phosphoniumylide produced by strong base such as butyllithium in solvents such astetrahydrofuran or toluene at temperatures between −78° C. and 0° C.followed by addition of the ketone of formula IV yields the desiredalkenes of formula XVI. The alkenes can then be reacted with a mixtureof silver cyanate and iodine in solvents such as diethyl ether ormixtures of ethyl acetate and acetonitrile. The resultantiodoisocyanates of formulas XVII can then be heated with alcohols liketert-butanol and a base like triethylamine or Huenig's base to yield theoxazolidinones of formula XVIII. Hydrolysis of the resultantoxazolidinone of formula XVIII with aqueous base like lithium hydroxideyields the aminoalcohol of formula VIII.

N-Acylation of the aminoalcohol of formula VIII can be effected bycondensation with halogenated acetic acid derivatives, such aschloroacetic acid using condensation reagents like benzotriazolederivatives, e.g.O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexa-fluorophosphate(HBTU) and the like in inert solvents, or with acid chloride derivativessuch as chloroacetylchloride in presence of a base such as triethylaminein an inert solvent both methods under conditions known to those skilledin the art and yielding acetyl derivatives of formula IX. Lactams offormula X can be prepared by cyclization of the alcohol of formula IXwith base, such as potassium tert-butylate, in solvents such astert-butanol at temperatures ranging from room temperature to reflux.

For the further transformation, the benzophenone imine derivative offormula XII is treated with Lawesson's reagent under conditions known tothose skilled in the art to yield the thiolactam of formula XIX.Cleavage of the benzophenone imine of formula XIX under acidicconditions to the aniline derivative XX followed by the synthesis ofamides of formula XXI can be performed by standard procedures such asalready described for scheme 2. Alternatively, the aniline derivative offormula XX can be obtained by treatment of the lactam of formula XIII(scheme 2) with Lawesson's reagent. Treatment of the thiolactam offormula XXI either with oxidizing reagents like tert-butyl hydroperoxidefollowed by ammonolysis or by treatment with ammonia in methanol aloneyields the final compound of formula I′.

A more precise description of the conditions is given in the preparationof Building block E.

Compounds of general formula I wherein X═S (I″) can be prepared byreaction of compounds of formula I′ with a thiation agent likeLawesson's reagent under conditions known to those skilled in the art toyield the corresponding thioamides of formula I″.

Compounds of formula I′″ can be prepared as follows: Starting from thethiolactam of formula XIX the reaction with a solution of ammonia in aprotic solvent such as methanol, ethanol or water, preferably methanol,with or without presence of a mild oxidant such astert-butylhydroperoxide at temperatures between 0 and 60° C., preferablyat 23° C. in the presence of an oxidant or at 50 to 60° C. in theabsence of an oxidant.

The intermediate benzophenone imine of formula XXII can be hydrolyzed tothe aniline of formula XXIII by aqueous mineral acid such as sulfuricacid or hydrochloric acid, preferably hydrochloric acid, in a solventsuch as tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane, preferably1,4-dioxane, at temperatures between 0 and 23° C., preferably at 23° C.

The selective condensation of anilines of formula XXIII with acids tocompounds of formula I′″ was achieved by the use of4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloridehydrate (DMTMM) as the condensating agent in a protic solvent such asmethanol or ethanol, preferably methanol, at temperatures between 0 and23° C., preferably at 4° C.

Compounds of formula I″″ can also be prepared as follows: Starting fromthe iminoether of formula XI the treatment with ammonium salts such asammonium chloride in a protic solvent like alcohols, preferablymethanol, yields the amine of formula XXIV.

The intermediate amine of formula XXIV can be protected by groups liketriphenylmethyl derivatives, preferably by 4,4′-dimethoxytriphenymethyl.The reaction can be performed in inert solvents, e.g. dichloromethane,at temperatures between 0° C. and room temperature to yield theN-protected amine of formula XXV.

The transformation into the aniline derivative of formula XXVII can beachieved by following the reaction sequence via the benzophenone iminederivative of formula XXVIII and its hydrolysis as described before.

The coupling of anilines of formula XXVII with acids to compounds offormula XXVIII can be achieved by appropriate coupling agents likecarbodiimides or uronium salts, such as for exampleN,N′-carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride (EDCI),O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate(TBTU) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU) under basic conditions, i.e. in the presenceof a base, preferably an alkylamine such as diisopropylethylamine ortriethylamine, or a tertiary amine such as N-methylmorpholine or4-(dimethylamino)-pyridine. The reaction is carried out in a suitablesolvent such as for example N,N-dimethylformamide (DMF),dimethylacetamide or dichloromethane, at temperatures between 0° C. andambient temperature. Furthermore by using4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloridehydrate (DMTMM) as the condensating agent in a protic solvent such asmethanol or ethanol, preferably methanol, at temperatures between 0 and23° C., preferably at 4° C.

The N-protecting group in compounds of formula XXVIII can be cleaved byacids like trifluoroacetic acid in inert solvents, e.g. dichloromethane,at temperatures between 0 and 23° C. to yield compounds of formula I″″.

Compounds of the general formula VIIIa can be prepared in anenantioselective manner as follows: An alpha-ketoester of generalformula XXIX can be converted into the sulfinyl imine of general formulaXXX in analogy to T. P. Tang & J. A. Ellman, J. Org. Chem. 1999, 64, 12,by condensation of the aryl ketone group and a sulfinamide, e.g. analkyl sulfinamide, in this case most preferably(S)-(−)-tert-butylsulfinamide in the presence of a Lewis acid such ase.g. a titanium(IV)alkoxide, more preferably titanium(IV)ethoxide in asolvent such as an ether, e.g. diethyl ether or more preferablytetrahydrofuran.

The conversion of the sulfinyl imine XXX to the ester of general formulaXXXI or directly to the alcohols of general formula XXXII proceedsstereoselectively by the chiral directing group as described by Tang &Ellman.

The sulfinyl imine of general formula XXX can be treated with anorganometallic reagent, e.g. an organolithium or Grignard-reagent, in asolvent such as an ether, e.g. diethyl ether or more preferablytetrahydrofuran, at temperatures starting from −78° C. and eventuallyraising to 23° C., to generate the esters of general formula XXXI.

These esters of general formula XXXI can in turn be treated with anotherorganometallic reagent, e.g. an organolithium or Grignard-reagent, in asolvent such as an ether, e.g. diethyl ether or more preferablytetrahydrofuran, at temperatures starting from −78° C. and eventuallyraising to 23° C., to generate the alcohols of general formula XXXII,wherein R¹ can be different from R⁴ and R⁵.

Alternatively the esters of general formula XXXI can be reduced to thealcohols of general formula XXXII, wherein R⁴ and R⁵ are hydrogen, byreaction with a reducing agent such as e.g. lithium aluminum hydride ormore preferably lithium borohydride in an ether solvent, like e.g.diethyl ether or more preferably tetrahydrofuran, at temperaturesbetween 0 and 50° C., preferably at 23° C. to yield aminoalcohols VIII.

If compounds of general formula XXXII, wherein R′, R⁴ and R⁵ are all ofthe same kind, are desired, the sulfinyl imine of general formula XXXcan be treated with a large excess of an organometallic reagent, e.g. anorganolithium or Grignard-reagent, in a solvent such as an ether, e.g.diethyl ether or more preferably tetrahydrofuran, at temperaturesstarting from −78° C. and eventually raising to 23° C., to directlygenerate the alcohols of general formula XXXII.

If compounds of general formula XXXII, wherein R′, R⁴ and R⁵ are all ofdifferent kind, are desired, the sulfinyl imine of the Weinreb amideinstead of the ethyl ester in general formula XXX (as described e.g. inJournal of Organic Chemistry (1995), 60(16), 5016-23) can besequentially (first introduction of R¹, then R⁴ and finally R⁵) treatedwith an organometallic reagent, e.g. an organolithium orGrignard-reagent, in a solvent such as an ether, e.g. diethyl ether ormore preferably tetrahydrofuran, at temperatures starting from −78° C.and each time eventually raising to 23° C., where after aqueous workupwith ammonium chloride solution of each step first the correspondingWeinreb amide instead of the ethyl ester of general formula XXXI, thenthe ketone bearing R¹ and R⁴ and finally the alcohols of general formulaXXXII are obtained.

Hydrolysis of the chiral directing group in the alcohols of generalformula XXXII to give the chiral amino alcohol of general formula VIIIcan be accomplished with a mineral acid, e.g. sulfuric acid orpreferably hydrochloric acid in a solvent such as an ether, e.g. diethylether, tetrahydrofuran or more preferably 1,4-dioxane.

As an alternative synthetic access to chiral amino alcohols of thegeneral formula VIII, the following route can be employed: Aromaticketones of general formula IV can be converted into the sulfinyl imineof general formula XXXIII in analogy to T. P. Tang & J. A. Ellman, J.Org. Chem. 1999, 64, 12, by condensation of the aryl ketone group and asulfinamide, e.g. an alkyl sulfinamide, in this case most preferably(R)-(+)-tert-butylsulfinamide in the presence of a Lewis acid such ase.g. a titanium(IV)alkoxide, more preferably titanium(IV)ethoxide in asolvent such as an ether, e.g. diethyl ether or more preferablytetrahydrofuran.

The conversion of the sulfinyl imine XXXIII to the nitrile of generalformula XXXIV proceeds stereoselectively by the chiral directing groupas described by Tang & Ellman or by A. Avenoza, J. H. Busto, F. Corzana,J. M. Peregrina, D. Sucunza, M. M. Zurbano in Synthesis 2005, (4),575-578.

The sulfinyl imine of general formula XXXIII can be treated with anmixed alkyl alkoxide aluminum cyanide reagent, e.g. ethylaluminiumcyanoisopropoxide [EtAl(O-i-Pr)CN], in a solvent such as an ether, e.g.diethyl ether or more preferably tetrahydrofuran, at temperaturesstarting from −78° C. and eventually raising to −10° C., to generate thenitriles of general formula XXXIV as described e.g. by A. Avenoza, J. H.Busto, F. Corzana, J. M. Peregrina, D. Sucunza, M. M. Zurbano inSynthesis 2005, (4), 575-578.

Hydrolysis of the chiral directing group in the nitriles of generalformula XXXIV to give first the chiral amino nitriles can beaccomplished with a mineral acid, e.g. sulfuric acid or preferablyhydrochloric acid in a solvent such as an ether, e.g. diethyl ether,tetrahydrofuran or more preferably 1,4-dioxane, which is followed byanother acidic reaction with a mineral acid, e.g. anhydrous hydrochloricacid or preferably sulfuric acid in a solvent such as an aliphaticalcohol, e.g. ethanol or more preferably methanol, at temperatures from23 to 80° C., to give the chiral amino esters of general formula XXXV.

The chiral amino esters of general formula XXXV can be treated with anorganometallic reagent, e.g. an organolithium or Grignard-reagent, in asolvent such as an ether, e.g. diethyl ether or more preferablytetrahydrofuran, at temperatures starting from −78° C. and eventuallyraising to 23° C., to generate the chiral amino alcohols of generalformula VIIIa.

Also chiral amino esters of general formula XXXV can be reduced to thechiral amino alcohols of general formula VIII, wherein R⁴ and R⁵ arehydrogen, by reaction with a reducing agent such as e.g. lithiumborohydride or more preferably lithium aluminum hydride in an ethersolvent, like e.g. diethyl ether or more preferably THF, at temperaturesbetween 0 and 50° C., preferably at 23° C.

The intermediate lactams of formula Xa can be obtained as follows:Selective N-protection of the aminoalcohol of formula VIII can beeffected by reductive amination with benzaldehydes, preferably with4-methoxybenzaldehyde, in presence of reducing agents like sodiumborohydride or sodium cyano borohydride, preferably sodiumtriacetoxyborohydride to give amines of formula)(XXVI.

Advantageously, the O-protection of compound)(XXVI can be effected by asilyl group, eg. tert-butyldimethylsilyl, cleavable by fluoride which atthe same time can later on act as a base in the cyclisation step ofcompounds of formula XXXVIII to yield compounds of formula XXXIX.

Beforehand, the N-acylation of the diprotected aminoalcohol of formulaXXXVII can be effected by condensation with halogenated propionic acidderivatives, optionally substituted in position 2 by R⁶ which has themeaning as defined above. Conditions for such condensation are known tothose skilled in the art, preferably Schotten-Baumann conditions foracid chlorides with e.g. chloroform as the organic solvent and sodiumhydrogen-carbonate as the aqueous base to form the biphasic system wereapplied to yield amides of formula XXXVIII.

Cleavage of the N-protecting group of compounds of formula XXXIX can beaccomplished preferably by strong acid, e.g. trifluoromethanesulfonicacid, in presence of anisole and with trifluoroacetic acid as thesolvent to yield the lactam of formula Xa

Alternatively, the intermediate lactams of formula Xa can be obtained bydirect selective N-acylation of the aminoalcohol of formula VIII withhalogenated propionic acid derivatives, optionally substituted inposition 2 by R⁶ which has the meaning as defined above. Reaction of thecorresponding acid chlorides in inert organic solvents, eg.tetrahydrofuran, dioxane, or acetonitrile, in presence of an organicbase, e.g. triethylamine, at temperatures between 0 and 23° C. yieldedamides of formula IXa.

The cyclization to lactams of formula Xa can be effected by treatment ofamides of formula IXa with a base, e.g. tert-butanolate, in solventssuch as tert-butanol at temperatures ranging from 10° C. to reflux.

Furthermore, lactams of formula Xa can be prepared by N-alkylation oflactams of formula X by treatment with benzylhalogenides such as4-methyoxybenzylhalogenide or 3,4-dimethoxybenzylhalogenide, preferably4-methyoxybenzylbromide, in presence of a base, e.g. tert-butanolate, ininert organic solvents like e.g. N,N-dimethylformamide to yieldN-protected lactams of formula XL.

Compounds of formula XXXIX can be obtained by treatment of compounds offormula XL with alkylating or benzylating agents, e.g. iodomethane orbenzylbromide, in presence of a base such as lithium diisopropylamide ininert solvents like e.g. tetrahydrofuran, dioxane, 1,2-dimethoxyethane,preferably tetrahydrofuran, at −75° C. The cleavage of the N-protectinggroup to compounds of formula Xa can be achieved as described before.

With the proviso that R³ is not F, compounds of formula Xa′ can beobtained by treatment of compounds of formula XXXIX with alkylating orbenzylating agents under conditions as described before.

For the further transformation to the corresponding aniline derivativesthe same procedures were applied as described before.

The corresponding pharmaceutically acceptable salts with acids can beobtained by standard methods known to the person skilled in the art,e.g. by dissolving the compound of formula I in a suitable solvent suchas e.g. dioxane or tetrahydrofuran and adding an appropriate amount ofthe corresponding acid. The products can usually be isolated byfiltration or by chromatography. The conversion of a compound of formulaI into a pharmaceutically acceptable salt with a base can be carried outby treatment of such a compound with such a base. One possible method toform such a salt is e.g. by addition of 1/n equivalents of a basic saltsuch as e.g. M(OH)_(n), wherein M=metal or ammonium cation and n=numberof hydroxide anions, to a solution of the compound in a suitable solvent(e.g. ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) andto remove the solvent by evaporation or lyophilisation.

Insofar as their preparation is not described in the examples, thecompounds of formula I as well as all intermediate products can beprepared according to analogous methods or according to the methods setforth herewithin. Starting materials are commercially available, knownin the art or can be prepared by methods known in the art or in analogythereto.

It will be appreciated that the compounds of general formula I in thisinvention can be derivatized at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.

Pharmacological Tests

The compounds of formula I and their pharmaceutically acceptable saltspossess valuable pharmacological properties. Compounds of the presentinvention are associated with inhibition of BACE1 and/or BACE2 activity.The compounds were investigated in accordance with the test givenhereinafter.

Assay A

Binding studies using SPR based methods

Instrumentation:

The binding assay is performed on an A100 SPR instrument fromGEHealthcare using a CM5 sensor chip.

Buffers:

BufferA: 10 mM acetate pH 4.5Buffer B: 10 mM acetate (pH 4.6), 150 mM NaCl, 3 mM EDTA, 0.05% P20Buffer C: 10 mM acetate (pH 4.6), 150 mM NaCl, 3 mM EDTA, 0.05% P20, 4%DMSO

Immobilisation of BACE1

Full length BACE-1 (6his-tagged full length BACE 1 expressed in SF9cells) is immobilized on one spot of the CM5 sensor chip applying thestandard amine coupling chemistry protocol recommended by the chipmanufacturer (GEHealthcare). The coupling kit of GEHealthcare (ordercode BR-1000-50) is used. Buffer B is used as the running buffer. Thecarboxylic acid groups on the CM5 sensor chip are activated bycontacting the surface with a mixture of N-hydroxysuccinimide (55.75mg/ml) and 1-ethyl-3-(3-diaminopropyl)-carbodiimide hydrochloride (375mg/ml) for 10 mM The activated surface is then contacted with a solutionof BACE-1 (100 μg/ml) dissolved in buffer A. The contact is terminatedas soon as the desired amount of protein (˜13000 RU corresponding to ˜13ng/mm2 of protein) is attached to the surface. Excess carbodiimide estergroups on the surface are quenched by contacting the surface for 7minutes with 1.0 M ethanolamine solution (pH 8.0).

Immobilisation of BACE2

BACE2 enzyme ectodomain (derived from plasmid “pET17b-T7-hu proBACE2”)was prepared as described in the art (Ostermann et al., “CrystalStructure of Human BACE2 in Complex with a HydroxyethylamineTransition-state Inhibitor”, Journal of Molecular Biology 2006, 355,249-261). BACE2 is immobilized on a one spot of the CM5 sensor chipapplying the standard amine coupling chemistry protocol recommended bythe chip manufacturer (GE Healthcare). The coupling kit of GE Healthcare(order code BR-1000-50) is used. Buffer B is used as the running buffer.The carboxylic acid groups on the CM5 sensor chip are activated bycontacting the surface with a mixture of N-hydroxysuccinimide (55.75mg/ml) and 1-ethyl-3-(3-diaminopropyl)-carbodiimide hydrochloride (375mg/ml) for 10 min. The activated surface is then contacted with asolution of BACE-2 (100 μg/ml) dissolved in buffer A. The contact isterminated as soon as the desired amount of protein (˜13000 RUcorresponding to ˜13 ng/mm2 of protein) is attached to the surface.Excess carbodiimide ester groups on the surface are quenched bycontacting the surface for 7 minutes with 1.0 M ethanolamine solution(pH 8.0).

Preparation of Sample Solutions for Binding Experiments

The compounds to be characterized by equilibrium binding constants andkinetic rate constants are dissolved in pure dimethylsulfoxide (10 mM).The dimethylsulfoxide solution is diluted into buffer B in a way toobtain the desired starting concentration of the concentration seriesand a final dimethylsulfoxide content of the solution of 4%. Aconcentration series (10 concentrations) is then produced from thisstock solution by diluting it with buffer C applying variable dilutionfactors of 1.0, 0.8, 0.75, 0.66, 0.5, 0.5, 0.5, 0.5, 0.5, 0.5; or 0.8,0.75, 0.66, 0.5, 0.5, 0.5, 0.5, 0.5, 0.5.

Binding Experiments

Binding experiments are performed using buffer C as the running buffer.The immobilized BACE1 and BACE2 proteins, respectively, are contacted inparallel with a flow (30 μl/min) of the sample solutions for 2 minutes.The binding reaction is monitored in real time. After the contact phasethe sensor chip is contacted again with running buffer and thedissociation of the samples is again monitored. After each sample of aconcentration series the sensor surface is extensively washed to removeall sample from the surface before starting a new binding experimentwith the next solution. After each concentration series the bindingactivity of the immobilized BACE1 and BACE2 proteins are controlled bymonitoring the binding curve of a known positive control sample.

Evaluation of the Binding Parameters from the Monitored Binding Curves

a) High affinity binders show often time resolved association anddissociation reactions. In this case the binding curves of aconcentration series are fitted with the differential equationdescribing the kinetics of a 1/1 binding reaction. The software package(Biaeval) provided by the instrument manufacturer is used. The kineticfit delivers the kinetic rate constants ka (M−1·s−1) and kd (s−1) andthe equilibrium binding constant KD(=koff/kon).b) Low affinity binders often show a fast association and a fastdissociation reaction that cannot be resolved by the instrument. In thiscase, equilibrium responses measured for the different concentrations ofa series at the end of the association phase are plotted against thelogarithms of the concentrations. The resulting curve is fitted with amathematical function using the Sigma plot fitting procedures. The fitdelivers in this case the KD value for the interaction and therespective Hill slope.

Exemplified compounds show K_(D) values <63 μM as shown in the tablebelow, most preferred are K_(D) values <20 μM.

Cellular Abeta-Lowering Assay:

Human HEK293 cells which are stably transfected with a vector expressinga cDNA of the human APP wt gene (APP695) were used to assess the potencyof the compounds in a cellular assay. The cells were seeded in 96-wellmicrotiter plates in cell culture medium (Iscove, plus 10% (v/v) fetalbovine serum, glutamine, penicillin/streptomycin) to about 80%confluence and the compounds were added at a 10× concentration in 1/10volume of medium without FCS containing 8% DMSO (final concentration ofDMSO was kept at 0.8% v/v). After 18-20 hrs incubation at 37° C. and 5%CO₂ in a humidified incubator the culture supernatant was harvested forthe determination of Aβ40 concentrations. 96well ELISA plates (e.g.,Nunc MaxiSorb) were coated with monoclonal antibody which specificallyrecognize the C-terminal end of Aβ40 (Brockhaus et al., NeuroReport 9,1481-1486; 1998). After blocking of non-specific binding sites with e.g.1% BSA and washing, the culture supernatants were added in suitabledilutions together with a horseradish peroxidase-coupled Aβ detectionantibody (e.g., antibody 4G8, Senetek, Maryland Heights, Mo.) andincubated for 5 to 7 hrs. Subsequently the wells of the microtiter platewere washed extensively with Tris-buffered saline containing 0.05% Tween20 and the assay was developed with tetramethylbenzidine/H₂O₂ in citricacid buffer. After stopping the reaction with one volume 1 N H₂SO₄ thereaction was measured in an ELISA reader at 450 nm wavelength. Theconcentrations of Aβ in the culture supernatants were calculated from astandard curve obtained with known amounts of pure Aβ peptide.

Assay for RACE Inhibition by Measuring Cellular TMEM27 Cleavage:

The assay uses the principle of inhibition of human TMEM27 cleavage byendogenous cellular BACE2 in the Ins1e rat cell line and shedding fromthe cell surface into the culture medium, followed by detection in anELISA assay. Inhibition of BACE2 prevents the cleavage and shedding in adose-dependent manner.

The stable cell line “INS-TMEM27” represents an INS1e-derived cell linewith inducible expression (using the TetOn system) of full-lengthhTMEM27 in a doxycycline-dependent manner. The cells are culturedthroughout the experiment in RPMI1640+Glutamax (Invitrogen)Penicillin/Streptomycin, 10% Fetal bovine serum, 100 mM pyruvate, 5 mMbeta-mercaptoethanol, 100 micrograms/ml G418 and 100 microgram/mlhygromycin and are grown in adherent culture at 37° C. in a standard CO₂cell culture incubator.

INS-TMEM27 cells are seeded in 96-well plates. After 2 days in culture,BACE2 inhibitor is added in a range of concentrations as required by theassay and after a further two hours, doxycycline is added to a finalconcentration of 500 ng/ml. The cells are incubated for a further 46hours and the supernatant harvested for detection of shed TMEM27.

An ELISA assay (using a pair of mouse anti-human-TMEM27 antibodies,raised against the extracellular domain of TMEM27) is used for detectionof TMEM27 in the culture medium. An EC₅₀ for BACE2 inhibition iscalculated using the ELISA readout for each inhibitor concentration withstandard curve-fitting software such as XLFit for the Excel spreadsheetprogram.

The assay readout is the initial rate of change of fluorescenceintensity giving a relative measure of BACE2 activity. Small valuescorrespond to high inhibition and larger values to low inhibition. Todetermine IC₅₀ values (i.e. the concentration inhibiting the enzymeactivity by 50%) of the compound for BACE2, typically, 12 assays weremade with a range of concentrations chosen empirically to give low, highand intermediate inhibition of the protease. IC₅₀ values were determinedusing these assay values generated for a range of inhibitorconcentrations and the curve fitting software XLfit (IDBS) using theSigmoidal Dose-Response Model.

The preferred compounds according to formula I have an inhibitoryactivity in the above cellular assay given as IC₅₀ value and in theabove assay A given as K_(D) values. Table 2 illustrates K_(D) and IC₅₀values of selected examples.

TABLE 2 K_(D) and IC₅₀ values for the interaction of selected examplesExam- ple BACE1 K_(D) BACE2 K_(D) BACE1 IC₅₀ BACE2 IC₅₀ No. [μM] [μM][μM] [μM] 1 0.320 0.044 0.120 0.021 2 0.050 0.009 0.016 0.048 3 1.6840.580 — 4 1.716 0.381 0.570 0.950 5 62.500 5.300 — — 6 6.900 0.230 1.5300.660 7 0.183 0.023 0.041 0.049 8 1.487 0.106 0.327 0.360 9 0.717 0.0630.058 0.043 10 3.301 0.361 — 11 0.490 0.044 0.041 — 12 — — 0.020 0.01713 0.445 0.033 0.024 0.051 14 33.000 5.400 — — 15 20.100 6.700 — — 161.408 0.513 — 18 0.034 0.004 0.006 0.031 19 0.394 0.098 0.130 0.837 200.050 0.008 0.003 0.006 21 0.017 0.004 0.003 0.002 22 0.140 0.019 0.0110.011 23 0.309 10.836 0.160 — 24 1.877 5.747 0.120 — 25 4.172 1.2200.410 — 26 — — 0.375 2.227 27 — — 1.130 0.320 28 0.071 0.011 0.019 0.05829 0.058 0.006 0.050 0.140 30 — — 0.023 — 31 — — 0.023 — 32 4.200 20.0000.670 — 33 0.077 0.141 0.026 — 34 0.003 0.003 0.004 0.004 35 0.028 0.0040.015 0.016 36 2.265 0.955 0.550 0.120 37 0.283 0.020 0.240 0.017 380.039 0.032 0.021 0.044 39 0.045 0.008 0.028 0.130 40 0.015 0.002 0.0130.002 41 0.054 0.006 0.026 0.004 42 0.208 2.550 0.190 — 43 0.085 0.0050.079 0.013 44 1.820 0.043 0.470 0.310 45 3.940 3.020 0.760 0.620 4610.750 0.629 1.350 0.720 47 — — 0.800 0.730 48 1.200 0.115 0.350 0.05249 0.015 0.022 0.004 0.066 50 0.900 2.100 0.039 1.400 51 0.022 0.0020.014 0.005 52 0.194 >10 1.180 — 53 3.950 1.220 0.620 0.910 54 >10 6.100— — 55 6.400 2.300 — 0.046 56 10.850 1.720 1.190 >10 57 >10 1.800 —0.320 58 >10 3.600 — — 59 9.600 4.000 — — 60 0.112 0.117 0.140 — 610.440 4.679 0.390 — 62 5.521 7.340 0.270 — 63 3.060 1.090 0.510 64 0.4837.820 0.660 — 65 2.473 1.12 0.180 — 66 0.173 0.159 0.680 — 67 0.0110.015 — — 68 — — 0.010 — 69 — — 0.009 — 70 1.100 0.045 — — 71 1.5006.000 — — 72 0.016 0.025 0.003 0.039 73 0.009 0.051 0.004 0.105 74 0.0100.002 0.004 1.354 75 0.261 2.150 0.110 >10 76 0.093 0.988 0.015 — 771.440 2.600 0.800 — 78 0.885 6.500 0.500 — 79 4.000 4.900 — — 80 2.2700.045 0.700 0.084 81 0.102 0.256 0.047 0.210 82 0.129 0.113 0.046 0.14083 0.916 0.276 0.300 0.130 84 0.261 0.077 0.140 0.083 85 >10 6.900 — —86 >10 3.600 — — 87 0.474 0.477 0.120 0.052 88 >10 3.450 2.760 0.560 890.805 — 0.500 0.820 90 0.148 0.150 0.220 1.220 91 0.994 1.140 1.4600.095 92 2.225 1.070 0.400 1.090 93 >10 3.850 6.820 3.390 94 2.700 1.9551.400 1.080 95 >10 3.600 — — 96 >10 6.100 — — 97 >10 1.760 — — 98 0.0140.004 0.007 0.001 99 0.046 0.008 0.017 0.003

Pharmaceutical Compositions

The compounds of formula I and the pharmaceutically acceptable salts canbe used as therapeutically active substances, e.g. in the form ofpharmaceutical compositions. Thus, the present invention also providespharmaceutical compositions containing compounds of the invention and apharmaceutically acceptable carrier. Such pharmaceutical compositionscan be in the form of tablets, coated tablets, dragées, hard and softgelatin capsules, solutions, emulsions or suspensions. Thepharmaceutical compositions also can be in the form of suppositories orinjectable solutions.

The pharmaceutical preparations can be administered orally, e.g. in theform of tablets, coated tablets, dragées, hard and soft gelatinecapsules, solutions, emulsions or suspensions. The administration can,however, also be effected rectally, e.g. in the form of suppositories,or parenterally, e.g. in the form of injection solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acids or its salts and thelike can be used, for example, as such carriers for tablets, coatedtablets, dragées and hard gelatine capsules. Suitable carriers for softgelatine capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Depending on the nature ofthe active substance no carriers are however usually required in thecase of soft gelatine capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, glycerol,vegetable oil and the like. Suitable carriers for suppositories are, forexample, natural or hardened oils, waxes, fats, semi-liquid or liquidpolyols and the like.

The pharmaceutical compositions can, moreover, contain pharmaceuticallyacceptable auxiliary substances such as preservatives, solubilizers,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorants, salts for varying the osmotic pressure, buffers, maskingagents or antioxidants. They can also contain still othertherapeutically valuable substances.

The present invention also provides a method for the manufacture ofpharmaceutical compositions. Such process comprises bringing one or morecompounds of formula I and/or pharmaceutically acceptable acid additionsalts thereof and, if desired, one or more other therapeuticallyvaluable substances into a galenical administration form together withone or more therapeutically inert carriers.

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, have to be adjusted to theindividual requirements in each particular case. In the case of oraladministration the dosage for adults can vary from about 0.01 mg toabout 1000 mg per day of a compound of general formula I or of thecorresponding amount of a pharmaceutically acceptable salt thereof. Thedaily dosage can be administered as single dose or in divided doses and,in addition, the upper limit can also be exceeded when this is found tobe indicated.

The following examples illustrate the present invention without limitingit, but serve merely as representative thereof. Examples of compositionsaccording to the invention are:

Example A

Tablets of the following composition are manufactured in the usualmanner

TABLE 3 Possible tablet composition mg/tablet ingredient 5 25 100 500compound of formula I 5 25 100 500 lactose anhydrous DTG 125 105 30 150Sta-Rx 1500 6 6 6 60 microcrystalline cellulose 30 30 30 450 magnesiumStearate 1 1 1 1 Total 167 167 167 831

Manufacturing Procedure

1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.2. Dry the granules at 50° C.3. Pass the granules through suitable milling equipment.4. Add ingredient 5 and mix for three minutes; compress on a suitablepress.

Example B-1

Capsules of the following composition are manufactured:

TABLE 4 Possible capsule ingredient composition mg/capsule ingredient 525 100 500 compound of formula I 5 25 100 500 hydrous lactose 159 123148 — corn starch 25 35 40 70 talk 10 15 10 25 magnesium stearate 1 2 25 Total 200 200 300 600

Manufacturing Procedure

1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.2. Add ingredients 4 and 5 and mix for 3 minutes.3. Fill into a suitable capsule.

The compound of formula I, lactose and corn starch are firstly mixed ina mixer and then in a comminuting machine. The mixture is returned tothe mixer, the talc is added thereto and mixed thoroughly. The mixtureis filled by machine into suitable capsules, e.g. hard gelatinecapsules.

Example B-2

Soft Gelatin Capsules of the following composition are manufactured:

TABLE 5 Possible soft gelatine capsule ingredient composition ingredientmg/capsule compound of formula I 5 yellow wax 8 hydrogenated soybean oil8 partially hydrogenated plant oils 34 soybean oil 110 Total 165

TABLE 6 Possible soft gelatine capsule composition ingredient mg/capsulegelatine 75 glycerol 85% 32 karion 83 8 (dry matter) titanium dioxide0.4 iron oxide yellow 1.1 Total 116.5

Manufacturing Procedure

The compound of formula I is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example C

Suppositories of the following composition are manufactured:

TABLE 7 Possible suppository composition ingredient mg/supp. compound offormula I 15 suppository mass 1285 Total 1300

Manufacturing Procedure

The suppository mass is melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C. Thereupon, the finely powdered compoundof formula I is added thereto and stirred until it has dispersedcompletely. The mixture is poured into suppository molds of suitablesize, left to cool; the suppositories are then removed from the moldsand packed individually in wax paper or metal foil.

Example D

Injection solutions of the following composition are manufactured:

TABLE 8 Possible injection solution composition ingredient mg/injectionsolution. compound of formula I  3 polyethylene glycol 400 150 aceticacid q.s. ad pH 5.0 water for injection solutions ad 1.0 ml

Manufacturing Procedure

The compound of formula I is dissolved in a mixture of PolyethyleneGlycol 400 and water for injection (part). The pH is adjusted to 5.0 byacetic acid. The volume is adjusted to 1.0 ml by addition of theresidual amount of water. The solution is filtered, filled into vialsusing an appropriate overage and sterilized.

Example E

Sachets of the following composition are manufactured:

TABLE 9 Possible sachet composition ingredient mg/sachet compound offormula I 50 lactose, fine powder 1015 microcrystalline cellulose(AVICEL PH 102) 1400 sodium carboxymethyl cellulose 14polyvinylpyrrolidon K 30 10 magnesium stearate 10 flavoring additives 1Total 2500

Manufacturing Procedure

The compound of formula I is mixed with lactose, microcrystallinecellulose and sodium carboxymethyl cellulose and granulated with amixture of polyvinylpyrrolidon in water. The granulate is mixed withmagnesium stearate and the flavoring additives and filled into sachets.

Experimental Part

The following examples are provided for illustration of the invention.They should not be considered as limiting the scope of the invention,but merely as being representative thereof.

Preparation of Building block A(RS)-5-(3-Amino-phenyl)-5-methyl-morpholin-3-one hydrochloride

a) (RS)-5-(3-Bromo-phenyl)-5-methyl-imidazolidine-2,4-dione

A mixture of 3-bromo-acetophenone (10.0 g, 50 mmol), potassium cyanide(4.96 g, 75 mmol), and ammonium carbonate (33.45 g, 348 mmol) in ethanol(65 ml) was heated in an autoclave at 120° C. for 16 h. For the workup,the reaction mixture was cooled to room temperature, then treated withwater (250 ml) and ethyl acetate (500 ml). The aqueous layer wasseparated and re-extracted with ethyl acetate (250 ml). The combinedorganic layers were washed twice with saturated sodium chloride solution(2×250 ml), thereafter dried over sodium sulfate, and evaporated atreduced pressure. There were obtained 13.2 g (98.6% of theory) of(RS)-5-(3-bromo-phenyl)-5-methyl-imidazolidine-2,4-dione as a whitesolid. The purity of the product allowed using it in the next stepwithout further purification. Mass (calculated) C₁₀H₉BrN₂O_(2[)269.099];(found) [M−H]⁻=267, [[M+2-H]⁻=269.

b) (RS)-2-Amino-2-(3-bromo-phenyl)-propionic acid methyl ester

A dispersion of (RS)-2-amino-2-(3-bromo-phenyl)-propionic acid methylester (12.81 g, 48 mmol) in 6 N sodium hydroxide solution (95.23 ml) washeated to reflux for 48 h. For the workup, the reaction mixture wascooled with ice and treated with hydrochloric acid (36.5%) until pH 1was reached. The mixture was evaporated to dryness at reduced pressure.The crude (RS)-2-amino-2-(3-bromo-phenyl)-propionic acid hydrochloridewas dispersed in methanol (500 ml) and cooled to 0° C. Within 12 minutesand under ice cooling, thionylchloride (18.02 ml, 246 mmol) was addeddropwise. After complete addition, the reaction mixture was heated toreflux for 60 h. For the workup, the reaction mixture was cooled to roomtemperature and evaporated at reduced pressure. The white residue wastreated with a mixture of water and ice (200 ml), triethylamine (16.5ml), and diethylether (500 ml). The resulting suspension was filtratedover Dicalite; thereafter the aqueous layer was separated andre-extracted with diethylether (250 ml). The combined organic layerswere washed with saturated sodium chloride solution (250 ml), dried oversodium sulfate, and evaporated at reduced pressure. There were obtained9.39 g (76.7% of theory) of (RS)-2-amino-2-(3-bromo-phenyl)-propionicacid methyl ester as a light yellow oil. The purity of the productallowed using it in the next step without further purification. Mass(calculated) C₁₀H₁₂BrNO_(2[)258.117]; (found) [M+H]⁺=258, [M+2-H]⁺=260.

c) (RS)-2-Amino-2-(3-bromo-phenyl)-propan-1-ol

A solution of the (RS)-2-amino-2-(3-bromo-phenyl)-propionic acid methylester (9.39 g, 36 mmol) in tetrahydrofuran (360 ml) was treatedportionwise at −5° C. with lithium aluminium hydride (1.41 g, 36 mmol;282 mg/2 min). After complete addition, stirring was continued at 0-5°C. for 30 minutes. For the workup, the reaction mixture was cooled to−7° C., and water (9 ml) was added dropwise. Thereafter, 2 N sodiumhydroxide solution (9 ml) was added and stirring continued for 15minutes at room temperature. They grey suspension was filtrated throughDicalite which was washed with tetrahydrofuran (200 ml). The filtratewas evaporated at reduced pressure. There were obtained 8.67 g of crude(RS)-2-amino-2-(3-bromo-phenyl)-propan-1-ol as colorless oil. The purityof the product allowed using it in the next step without furtherpurification. Mass (calculated) C₉H₁₂BrNO [230.106]; (found) [M+H]⁺=230,[M+2-H]⁺=232.

d)(RS)—N-[1-(3-Bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide

A solution of crude (RS)-2-amino-2-(3-bromo-phenyl)-propan-1-ol (8.38 g,36 mmol) and triethylamine (6.08 ml, 44 mmol) in acetonitrile (140 ml)was treated dropwise at −2° C. with chloroacetylchloride (3.25 ml, 40mmol). After complete addition, the orange colored solution was left towarm to room temperature and stiffing was continued for 2 h. For theworkup, to the reaction was added silica gel (10 g) and it wasevaporated at reduced pressure, thereafter, it was purified bychromatography on silica gel using a gradient ofdichloromethane/methanol=100/0 to 90/10 as the eluent. There wereobtained 9.62 g (86% of theory) of(RS)—N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamideas a light brown oil. Mass (calculated) C₁₁H₁₃BrClNO_(2 [)306.589];(found) [M+H]⁺=306, [M+2-H]⁺=308.

e) (RS)-5-(3-Bromo-phenyl)-5-methyl-morpholin-3-one

A solution of(RS)—N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide(5.36 g, 17 mmol) in 2-methyl-2-butanol (100 ml) was treated in oneportion with potassium tert-butylate (6.66 g, 58 mmol). Initially, thetemperature rose to 30° C.; the reaction mixture was left to cool toroom temperature and stiffing was continued for one hour. For theworkup, the reaction mixture was treated with methanol (50 ml), thenevaporated at reduced pressure. The residue was purified bychromatography on silica gel using a gradient ofdichloromethane/methanol=100/0 to 75/25 as the eluent. There wereobtained 4.18 g (88% of theory) of(RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one as a white solid. Mass(calculated) C₁₁H₁₂BrNO_(2[)270.128]; (found) [M+H]⁺=270, [M+2-H]⁺==272.

f) (RS)-5-[3-(Benzhydrylidene-amino)-phenyl]-5-methyl-morpholin-3-one

A dried pressure tube was charged consecutively under an argonatmosphere with a solution of(RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (4.17 g, 15 mmol) intoluene (100 ml), sodium tert-butylate (4.586 g, 46 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl(tert-butyl-x-phos) (0.675 g, 1.6 mmol),tris(dibenzylideneacetone)-dipalladium chloroform complex (0.494 g, 0.5mmol), and benzophenone imine (5.88 g, 31 mmol). The sealed pressuretube was heated at 105° C. for 2.5 days. After cooling, the reactionmixture was evaporated to dryness and directly purified bychromatography on an Isolute flash NH₂ column using a gradient ofheptane/ethyl acetate=100/0 to 33/66 as the eluent. There were obtained5.67 g (99% of theory) of(RS)-5-[3-(benzhydrylidene-amino)-phenyl]-5-methyl-morpholin-3-one as ayellow foam. Mass (calculated) C₂₄H₂₂N₂O_(2[)370.455]; (found)[M+H]⁺=371.

g) (RS)-5-(3-Amino-phenyl)-5-methyl-morpholin-3-one Hydrochloride

A solution of(RS)-5-[3-(benzhydrylidene-amino)-phenyl]-5-methyl-morpholin-3-one (5.62g, 15 mmol) in dioxane (75 ml) was cooled to 15° C. and treated dropwisewith 1 N hydrochloric acid (18 ml). The reaction mixture was stirred atroom temperature overnight. For the workup, the reaction mixture wasevaporated at reduced pressure, and the residue was portioned betweendiethylether (120 ml) and 1 N hydrochloric acid (20 ml). The aqueousphase was separated and washed with diethylether (120 ml). Thisprocedure was repeated twice. The combined aqueous layers wereevaporated at reduced pressure, and 3.27 g (88% of theory) of(RS)-5-(3-amino-phenyl)-5-methyl-morpholin-3-one hydrochloride wereobtained as a yellowish solid used in the next step without furtherpurification. Mass (calculated) C₁₁H₁₅ClN₂O₂[242.707]; (found)[M+H]⁺=207.

Preparation of Building block B(R)-5-(3-Amino-phenyl)-5-methyl-morpholin-3-one Hydrochloride

a)(R)-(+)-N-[1-(3-Bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamideand(S)-(−)-N-[1-(3-Bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide

A solution of(RS)—N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide(8.0 g) in dichloromethane was divided in 200 mg aliquots which wereseparated on chiral HPLC (Reprosil Chiral NR 8 μm, 250×30 mm, Dr.MaischGmbH) using a 80:20-mixture of heptane and isopropanol as the eluent.The first eluting enantiomer (retention time: 9.40 min), the

(S)-(−)-N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide,was obtained as a viscous, colorless oil (3.30 g, 41% of theory), andthe second eluting enantiomer (retention time: 14.14 min), the(R)-(+)-N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide,was also obtained as a viscous, colorless oil (3.62 g, 45% of theory),withe.e. >99.5% each.

b) (R)-5-(3-Amino-phenyl)-5-methyl-morpholin-3-one Hydrochloride

In close analogy to the reaction sequence described for the preparationof Building block A, the cyclization of the(R)—N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamidewith potassium tert-butylate, followed by the palladium-catalyzedamination, and, finally, by the hydrolysis yielded the(R)-5-(3-amino-phenyl)-5-methyl-morpholin-3-one hydrochloride as a lightyellow solid. Mass (calculated) C₁₁H₁₅ClN₂O₂ [242.707]; (found)[M+H]⁺=207.

The (S)-5-(3-amino-phenyl)-5-methyl-morpholin-3-one was obtained in thesame manner.

Preparation of Building block C(RS)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-morpholin-3-one hydrochloride

In a reaction sequence analogous to that described for the preparationof Building block A,(RS)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one was obtainedas follows:

a) 1-(5-Bromo-2-fluoro-phenyl)-ethanone

A solution of 5-bromo-2-fluoro-benzoic acid (3.50 g, 16 mmol) indichloromethane (70 ml) was cooled to 0° C. and treated withtriethylamine (1.725 g, 17 mmol),N-(3-dimethylamino-propyl)-N′-ethyl-carbodiimide hydrochloride (3.032 g,16 mmol), 4-dimethylamino-pyridine (0.097 g, 0.8 mmol), andN,O-dimethyl-hydroxylamine (1.774 g, 18 mmol). The reaction mixture wasleft to warm to room temperature and stirred for 16 hours. For theworkup, the reaction mixture was diluted with dichloromethane (100 ml)and, consecutively, extracted with water (50 ml), citric acid (10%, 50ml), and saturated sodium hydrogen-carbonate solution (50 ml). Theorganic layer was dried over sodium sulfate, then evaporated. The crude5-bromo-2-fluoro-N-methoxy-N-methyl-benzamidematerial (3.73 g, 91% oftheory) was sufficiently pure and was directly engaged in the next step.In a dried flask, a solution of methylmagnesium chloride (3M intetrahydrofuran, 5.69 ml, 17 mmol) in tetrahydrofuran (24 ml) wastreated at 12-16° C. with a solution of5-bromo-2-fluoro-N-methoxy-N-methyl-benzamide (3.73 g, 14.2 mmol) intetrahydrofuran (24 ml). After complete addition, the reaction mixturewas heated to reflux. After 20 minutes, the white suspension wasquenched under ice cooling with a saturated solution of ammoniumchloride (25 ml). After dilution with ethyl acetate (50 ml), the aqueouslayer was separated and re-extracted with ethyl acetate (50 ml). Thecombined organic layers were washed with brine (20 ml), dried oversodium sulfate, and evaporated at reduced pressure.1-(5-bromo-2-fluoro-phenyl)-ethanone was obtained as a light yellowsolid (2.6 g, 84% of theory), which was directly engaged in the nextstep. R_(f): 0.55 (silica gel; eluent: heptane/ethyl acetate=4/1).

b) (RS)-5-(5-Bromo-2-fluoro-phenyl)-5-methyl-imidazolidine-2,4-dione

The reaction of 1-(5-bromo-2-fluoro-phenyl)-ethanone with potassiumcyanide and ammonium carbonate in ethanol in an autoclave at 120° C. for16 h yielded the title compound as light yellow solid. Mass (calculated)C₁₀H₈BrFN₂O_(2[)287.087]; (found) [M−H]⁻=285, [M+2-H]⁻=287.

c) (RS)-2-Amino-2-(5-bromo-2-fluoro-phenyl)-propionic acid methylester

The hydrolysis of the(RS)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-imidazolidine-2,4-dione with 6N sodium hydroxide solution and esterification of the resulting(RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propionic acid with methanoland thionylchloride yielded the(RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propionic acid methylester as alight yellow oil. The purity of the product allowed using it in the nextstep without further purification. Mass (calculated)C₁₀H₁₁BrFNO_(2[)276.107]; (found) [M+H]⁺=276, [M+2-H]⁺=278.

d) (RS)-2-Amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol

The reduction of the (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propionicacid methylester with lithium aluminium hydride in tetrahydrofuranyielded the (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol as alight yellow oil. The purity of the product allowed using it in the nextstep without further purification. Mass (calculated) C₉H₁₁BrFNO[248.097]; (found) [M+H]⁺=248, [M+2-H]⁺=250.

e)(RS)—N-[1-(5-Bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide

The acylation of the(RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol withchloroacetylchloride in acetonitrile yielded, after chromatography onsilica gel using a gradient of dichloromethane/methanol=100/0 to 80/20as the eluent, the(RS)—N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamideas a light brown waxy solid. Mass (calculated)C₁₁H₁₂BrClFNO_(2[)324.579]; (found) [M+H]⁺=324, [M+2-H]⁺=326.

f) (RS)-5-(5-Bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one

The cyclization of the(RS)—N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamidewith potassium tert-butylate yielded, after chromatography on silica gelusing a gradient of dichloromethane/methanol=100/0 to 80/20 as theeluent, the (RS)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one asa yellow waxy solid. Mass (calculated) C₁₁H₁₁BrFNO_(2[)288.118]; (found)[M+H]⁺=288, [M+2-H]⁺=290.

g)(RS)-5-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one

The amination of the(RS)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one with sodiumtert-butylate, tert-butyl-x-phos, tris(dibenzylideneacetone)-dipalladiumchloroform complex, and benzophenonimine in toluene yielded, afterchromatography on an Isolute flash NH₂ column using a gradient ofheptane/ethyl acetate=100/0 to 40/60 as the eluent, the(RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-oneas a yellow oil. Mass (calculated) C₂₄H₂₁FN₂O_(2[)388.446]; (found)[M+H]⁺=389.

h) (RS)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-morpholin-3-onehydrochloride

The hydrolysis of the(RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-oneyielded the (RS)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholin-3-onehydrochloride as a light yellow solid used in the next step withoutfurther purification. Mass (calculated) C₁₁H₁₄ClN₂O_(2[)260.698];(found) [M+H]⁺=225.

Preparation of Building block D(R)-(+)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-morpholin-3-onehydrochloride

a)(R)-(+)-N-[1-(5-Bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamideand(S)-(−)-N-[1-(5-Bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide

A solution of(RS)—N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide(2.7 g) in dichloromethane was divided in 100 mg aliquots which wereseparated on chiral HPLC (Reprosil Chiral NR 8 μm, 250×30 mm, Dr.MaischGmbH) using a 85:15-mixture of heptane and isopropanol as the eluent.The first eluting enantiomer (retention time: 9.94 min), the(S)-(−)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide,was obtained as a light yellow waxy solid (1.05 g, 39% of theory), andthe second eluting enantiomer (retention time: 12.92 min), the(R)-(+)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide,was also obtained as a light yellow waxy solid (1.07 g, 40% of theory),with e.e. >99% each.

b) (R)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-morpholin-3-onehydrochloride

In close analogy to the reaction sequence described for the preparationof Building block C, the cyclization of the(R)—N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamidewith potassium tert-butylate, followed by the palladium-catalyzedamination, and, finally, by the hydrolysis yielded the(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholin-3-one hydrochlorideas a light yellow solid. Mass (calculated) C₁₁H₁₄ClN₂O_(2[)260.698];(found) [M+H]⁺=225.

The (S)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholin-3-onehydrochloride was obtained in the same manner.

Preparation of Building block E(RS)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione

a) (5-Bromo-2-fluoro-phenyl)-cyclopropyl-methanone

In an analogous manner to that described for the preparation of Buildingblock C [a)], the reaction of5-bromo-2-fluoro-N-methoxy-N-methyl-benzamide with cyclopropylmagnesiumbromide in tetrahydrofuran yielded the title compound as a light yellowliquid; (HPLC 2.783 min 100%). Mass (calculated) C₁₀H₈BrFO [243.074];(found) [M+H]⁺=243, [M+2-H]⁺=245.

b) 4-Bromo-2-(1-cyclopropyl-vinyl)-1-fluoro-benzene

A suspension of methyltriphenylphosphonium bromide (7.142 g, 20 mmol) intoluene (50 ml) was treated with potassium amylate (1.7 M in toluene,11.76 ml, 20 mmol), and the mixture was stirred at 0° C. for 30 minutes.A solution of (5-bromo-2-fluoro-phenyl)-cyclopropyl-methanone (4.05 g,17 mmol) in toluene (17 ml) was added and the mixture stirred at roomtemperature for 2 hours. For the workup, the mixture was extracted withwater and ethyl acetate, the organic layer separated, dried andevaporated at reduced pressure. After chromatography on silica gel usinga mixture of hexane and ethyl acetate as the eluent, the4-bromo-2-(1-cyclopropyl-vinyl)-1-fluoro-benzene was obtained as yellowoil (3.816 g, 95% of theory). Mass (calculated) C₁₁H₁₀BrF [241.102];(found) [M+H]⁺=241, [M+2-H]⁺=243.

c)(RS)-4-Bromo-2-(1-cyclopropyl-2-iodo-1-isocyanato-ethyl)-1-fluoro-benzene

To a suspension of 4-bromo-2-(1-cyclopropyl-vinyl)-1-fluoro-benzene (3.8g, 16 mmol) and freshly prepared silver cyanate (2.835 g, 19 mmol) inethyl acetate (8 ml) and acetonitrile (16 ml) was added dropwise within1 hour at 0° C. in the dark a solution of iodine (4.4 g, 17 mmol) inethyl acetate (24 ml). Stirring was continued at 0° C. for 1.5 hours,then at 23° C. for 1 hour. The precipitate was filtered off, washed withethyl acetate. The filtrate was washed with an aqueous solution ofsodium sulfite (1%, 50 ml), the organic layer separated, dried oversodium sulfate, then evaporated at reduced pressure. The title compoundwas obtained as yellow oil (6.4 g, 100% of theory) which was used in thenext step without further purification.

d) (RS)-4-(5-Bromo-2-fluoro-phenyl)-4-cyclopropyl-oxazolidin-2-one

A solution of the crude(RS)-4-bromo-2-(1-cyclopropyl-2-iodo-1-isocyanato-ethyl)-1-fluoro-benzene(6.40 g, 16 mmol) in tert-butanol (200 ml) was treated at 23° C. withtriethylamine (2.16 ml, 16 mmol) and the mixture was stirred overnightat reflux. For the workup, the reaction mixture was evaporated atreduced pressure to yield the crude title compound as a yellow oil whichwas directly used in the next step. Mass (calculated)C₁₂H₁₁BrFNO_(2[)300.126]; (found) [M+H]⁺=300, [M+2-H]⁺=302.

e) (RS)-2-Amino-2-(5-bromo-2-fluoro-phenyl)-2-cyclopropyl-ethanol

A solution of the crude(RS)-4-(5-bromo-2-fluoro-phenyl)-4-cyclopropyl-oxazolidin-2-one (4.802g) in ethanol (25 ml) and water (125 ml) was treated with lithiumhydroxide monohydrate (6.7 g, 160 mmol) and the reaction mixture wasstirred at 100° C. overnight. For the workup, the reaction mixture wasextracted with dichloromethane, the combined organic layers were washedwith water, then dried over sodium sulfate and evaporated. The crudeproduct was purified by chromatography on an Isolute flash NH₂ columnusing a gradient of heptane/ethyl acetate as the eluent.(RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-2-cyclopropyl-ethanol wasobtained as a yellow oil (2.27 g, 52% of theory). Mass (calculated)C₁₁H₁₃BrFNO [274.132]; (found) [M+H]⁺=274, [M+2-H]⁺=276.

f)(RS)—N-[1-(5-Bromo-2-fluoro-phenyl)-1-cyclopropyl-2-hydroxy-ethyl]-2-chloro-acetamide

(RS)-2-Amino-2-(5-bromo-2-fluoro-phenyl)-2-cyclopropyl-ethanol (2.27 g,8 mmol) was dissolved in a mixture of dichloromethane (85 ml) and asaturated aqueous solution of sodium hydrogen-carbonate (85 ml). Thebiphasic mixture was then treated with a solution ofchloroacetylchloride (0.69 ml, 8.7 mmol) in dichloromethane. Thereaction mixture was stirred at room temperature and the progress of thetransformation checked by chromatography. After completion, the reactionmixture was diluted with dichloromethane, the organic layer separatedand washed with water, then dried over sodium sulfate and evaporated.The(RS)—N-[1-(5-bromo-2-fluoro-phenyl)-1-cyclopropyl-2-hydroxy-ethyl]-2-chloro-acetamidewas obtained as a yellow oil (2.73 g, 94.0% of theory). Mass(calculated) C₁₃H₁₄BrClFNO_(2[)350.614]; (found) [M+H]⁺=350,[M+2-H]⁺=352, [M+4-H]⁺=354.

g) (RS)-5-(5-Bromo-2-fluoro-phenyl)-5-cyclopropyl-morpholin-3-one

In an analogous manner to that described for the preparation of Buildingblock A [e)], the cyclization of(RS)—N-[1-(5-bromo-2-fluoro-phenyl)-1-cyclopropyl-2-hydroxy-ethyl]-2-chloro-acetamidewith potassium tert-butoxide in tert-butanol at room temperatureovernight yielded the(RS)-5-(5-bromo-2-fluoro-phenyl)-5-cyclopropyl-morpholin-3-one as ayellow oil (2.146 g, 88% of theory). Mass (calculated)C₁₃H₁₃BrFNO_(2[)314.153]; (found) [M+H]⁺=314, [M+2-H]⁺=316.

h)(RS)-5-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-5-cyclopropyl-morpholin-3-one

In an analogous manner to that described for the preparation of Buildingblock A [f)], the palladium-catalyzed amination of(RS)-5-(5-bromo-2-fluoro-phenyl)-5-cyclopropyl-morpholin-3-one withbenzophenonimine yielded the(RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-cyclopropyl-morpholin-3-oneas a yellow foam. Mass (calculated) C₂₆H₂₃FN₂O_(2[)414.478]; (found)[M+H]⁺=415.

i)(RS)-5-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-5-cyclopropyl-morpholine-3-thione

A mixture of(RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-cyclopropyl-morpholin-3-one(2.10 g, 5.07 mmol) and Lawesson's reagent (0.926 mg, 2.3 mmol) intetrahydrofuran (15 mL) was stirred at 70° C. for 3 hours. For theworkup, the reaction mixture was diluted with ethyl acetate andextracted with a saturated solution of sodium hydrogen-carbonate. Theorganic layer was dried over sodium sulfate and evaporated. The crudeproduct was purified by chromatography on silica gel using a gradient ofhexane/ethyl acetate as the eluent. The(RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-cyclopropyl-morpholine-3-thionewas obtained as a yellow foam (1.42 g, 65% of theory). Mass (calculated)C₂₆H₂₃FN₂OS [430.545]; (found) [M+H]⁺=431.

j) (RS)-5-(5-Amino-2-fluoro-phenyl)-5-cyclopropyl-morpholine-3-thione

A solution of(RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-cyclopropyl-morpholine-3-thione(1.42 g, 3.3 mmol) in dioxane (15 ml) and 1 M HCl (5 ml) was stirred atroom temperature for 30 minutes. The reaction mixture was poured on asaturated solution of sodium hydrogen-carbonate and extracted twice withethyl acetate. The combined organic layers were washed with brine, driedover sodium sulfate, filtered and evaporated at reduced pressure. Theresidue was purified by chromatography on silica gel using a 3:1-mixtureof dichloromethane and ethyl acetate as the eluent. CH₂Cl₂/EtOAc 3:1.The (RS)-5-(5-amino-2-fluoro-phenyl)-5-cyclopropyl-morpholine-3-thionewas obtained as a white solid (0.810 g, 92% of theory). Mass(calculated) C₁₃H₁₅FN₂OS [266.338]; (found) [M+H]⁺=267.

Preparation of Building block F(RS)-5-(3-Amino-phenyl)-5-methyl-morpholine-3-thione

Lawesson's reagent (0.69 g, 1.64 mmol, 1.3 eq.) was added in one portionto a suspension of 5-(3-amino-phenyl)-5-methyl-morpholin-3-one (0.26 g,1.26 mmol) in 1,2-dimethoxyethane (10 ml); the reaction mixture wasstirred at 80° C. for 18 hours. After complete conversion, the solventwas partially removed at reduced pressure and the dark orange oildiluted with dichloromethane (5 ml) before washing with 1 M HCl (2×5ml). The aqueous phase was brought to pH 8 and extracted withdichloromethane (4×10 ml) to yield the(RS)-5-(3-amino-phenyl)-5-methyl-morpholine-3-thione as a yellow oil(0.16 g, 57% of theory). Mass (calculated) C₁₁H₁₄N₂OS [222.31]; (found)[M+H]⁺=223.

Preparation of Building block G(RS)-3-(3-Bromo-phenyl)-5-methoxy-3-methyl-3,6-dihydro-2H [1,4]oxazine

In a vacuum dried flask under an argon atmosphere, a solution of(RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (3.0 g, 11.1 mmol) indichloromethane (145 ml) was treated with trimethyloxoniumtetrafluoroborate (2.594 g, 17 mmol). The reaction mixture was stirredat room temperature for 17 hours. For the workup, the incompletereaction was extracted with a saturated solution of sodiumhydrogen-carbonate (70 ml). The organic layer was dried over sodiumsulfate and evaporated. There were obtained 3.12 g of the title compoundas light yellow oil containing about 17% of the starting lactam. Mass(calculated) C₁₂H₁₄BrNO_(2[)284.16]; (found) [M+H]⁺=284, [M+2-H]⁺=286.

Preparation of Building block H

(R)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione

a)(R)-5-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one

As described for the preparation of Building block D, the cyclization ofthe(R)—N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamidewith potassium tert-butylate, followed by the palladium-catalyzedamination yielded the(R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-oneas a yellow solid. Mass (calculated) C₂₄H₂₁FN₂O_(2[)388.45]; (found)[M+H]⁺=389.

b)(R)-5-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholine-3-thione

A solution of(R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one287 mg, 0.7 mmol) in dioxane (4 ml) was treated with Lawesson's reagent(181 mg, 0.5 mmol). After heating at 80° C. for 16 hours the reactionmixture was evaporated at reduced pressure. The residue was directlypurified by chromatography on an Isolute flash NH₂ column using agradient of heptane and ethyl acetate=100/0 to 40/60 as the eluent. Thetitle compound was obtained as yellow foam (181 mg, 61.5% of theory).Mass (calculated) C₂₄H₂₁FN₂OS [404.507]; (found) [M+H]⁺=405.

c) (R)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione

In a manner analogous to the preparation of Building block E thehydrolysis of(R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholine-3-thionewith hydrochloric acid yielded the title compound as a light brown foam.Mass (calculated) C₁₁H₁₃FN₂OS [240.301]; (found) [M+H]⁺=241.

Preparation of Building block I(RS)-[5-(3-Amino-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine

a) (RS)-5-(3-Bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

In a vacuum dried flask under an argon atmosphere, a solution of5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (7.4 g, 27.4 mmol) indichloromethane (80 ml) was treated with trimethyloxoniumtetrafluoroborate (11.6 g, 3 eq). The reaction mixture was stirred atroom temperature overnight. The LC-MS profile showed partial conversioninto the desired compound so another 1.5 eq of trimethyloxoniumtetrafluoroborate were added and the reaction mixture was stirred atroom temperature overnight. For the workup, the reaction mixture waswashed with a saturated solution of sodium hydrogen-carbonate (50 ml).The organic layer was dried over sodium sulfate and evaporated. Thecrude product was dissolved in methanol (60 ml) in a micro reactor andammonium chloride (7.4 g, 5.3 eq) was added. The reaction mixture washeated at 100° C. for 16 hours. After cooling, the reaction mixture wasfiltered and evaporated to dryness, taken up with dichloromethane (30ml) and filtered again. The solvent was removed and the residue waspassed through a SCX (50 g) cartridge, washed with adichloromethane/methanol mixture and the product was recovered elutingwith a solution 2.0 M of ammonia in methanol. The(RS)-5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylaminewas obtained as a brown oil (3.7 g, 53% of theory). Mass (calculated)C₁₁H₁₃BrN₂O [269.14]; (found) [M+H]⁺=271.

b)(RS)-[Bis-(4-methoxy-phenyl)-phenyl-methyl]-[5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-amine

A solution of(RS)-5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(3.7 g, 13.8 mmol) and triethylamine (1.5 g, 1.1 eq) in dichloromethane(20 ml) was cooled to 0° C. and 4,4′-dimethoxytriphenylmethyl chloride(5.12 g, 1.1 eq) was added. The reaction mixture was stirred at roomtemperature overnight. Thereafter, water was added to the mixture andthe organic phase was separated, dried over sodium sulfate andconcentrated at reduced pressure. The crude was purified bychromatography on silica gel to yield the(RS)-[bis-(4-methoxy-phenyl)-phenyl-methyl]-[5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-amineas a yellow oil (7.0 g, 99% of theory). Mass (calculated)C₃H₃₁BrN₂O_(3[)571.52]; (found) [M+H]⁺=571.

c)(RS)-[5-(3-Amino-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine

Following the general procedure described below the palladium-catalyzedamination of(RS)-[bis-(4-methoxy-phenyl)-phenyl-methyl]-[5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-aminefollowed by the hydrolysis of the intermediate(RS)-{5-[3-(benzhydrylidene-amino)-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl}-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amineyielded the title compound. Mass (calculated) C₃₂H₃₃N₃O₃[507.64];(found) [M+H]⁺=508.

General procedure: Under an inert atmosphere of nitrogen to a mixture ofthe bromo-derivative (3 mmol), tert-butanolate (8 mmol),tert-butyl-x-phos (0.3 mmol), and tris(dibenzylideneacetone)-dipalladiumchloroform complex (0.1 mmol) were added benzophenonimine (5 mmol) anddry toluene (20 ml). The mixture was heated at 105° C. for 48 h and thenallowed to cool to room temperature. Water (10 ml) and dichloromethane(10 ml) were added, the organic layer was separated, washed with water(2×5 ml), dried over sodium sulfate, and evaporated. The crude productwas dissolved in 1,4-dioxane (18 ml) and hydrochloric acid (1 M, 6 ml)was added dropwise. The reaction mixture was stirred at room temperatureovernight. For the workup, the solvent was removed, the residue wassuspended in diethyl ether (10 ml) and washed with hydrochloric acid (6N). The aqueous phase was separated and extracted with diethylether(2×50 ml). The pH of the aqueous phase was adjusted to 14 using solidsodium hydroxide and the desired product was extracted withdichloromethane (3×50 ml). The organic layer was separated, dried oversodium sulfate and evaporated. The crude product was purified bychromatography on SCX-column and silica column using a mixture of ethylacetate and cyclohexane as the eluent.

Preparation of Building block J[(R)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine

a) (R)-5-(5-Bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one

In close analogy to the reaction sequence described for the preparationof Building block C, the cyclization of the(R)—N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide(see preparation Building block D) with potassium tert-butylate yieldedthe title compound as a light yellow solid (85% of theory). Mass(calculated) C₁₁H₁₁BrFNO_(2[)286.99]; (found) [M+H]⁺=287, [M+2-H]⁺=289.

b)(R)-5-(5-Bromo-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

In analogy to step a) in the synthesis of Building block I, thetreatment of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-onefollowed by the nucleophilic substitution with ammonium chloride yieldedthe title compound; its hydrochloride was obtained as a white solid (74%of theory). Mass (calculated) C₁₁H₁₂BrFN₂O [287.13]; (found) [M+H]⁺=287,[M+2-H]⁺=289.

c)[Bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-amine

In analogy to step c) in the synthesis of Building block I, the reactionof(R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylaminewith 4,4′-dimethoxytriphenylmethyl chloride yielded the title compoundas a white solid (72% of theory). Mass (calculated)C₃₂H₃₀BrFN₂O_(3[)589.51]; (found) [M+H]⁺=589, [M+2-H]⁺=591.

d)[(R)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine

Following the general procedure described above [Building block I stepc)] the palladium-catalyzed amination of[bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-aminefollowed by the hydrolysis of the intermediate benzhydrylidenederivative yielded the title compound (75% of theory). Mass (calculated)C₃₂H₃₂FN₃O_(3[)525.63]; (found) [M+H]⁺=526.

Preparation of Building block K(R)-5-(5-Amino-2-fluoro-phenyl)-5,6,6-trimethyl-morpholine-3-thione

a) (5-Bromo-2-fluoro-phenyl)-oxo-acetic acid ethyl ester

A solution of 4-bromo-1-fluoro-2-iodobenzene (6.3 g, 20.9 mmol) intetrahydrofuran (100 ml) was treated dropwise with isopropylmagnesiumchloride solution (2 M in tetrahydrofuran, 11.5 ml, 23 mmol) at −40° C.to −30° C. The light brown solution was stirred for 30 min at −30° C.Then diethyl oxalate (5.68 ml, 42.0 mmol) was added in one portion at−70° C. (rise of temperature to −55° C.). The cooling bath was removedand the brown-yellow solution was warmed up under stirring to −10° C.during 1 hour. The light brown suspension was poured on ice-coldhydrochloric acid (1 M) and extracted twice with ethyl acetate. Theorganic layers were washed with water and brine, dried over sodiumsulfate, and evaporated at reduced pressure to give 8 g of a yellowliquid. After chromatography on silica gel using a gradient ofcyclohexane and dichloromethane=100/0 to 70/30 as the eluent the(5-bromo-2-fluoro-phenyl)-oxo-acetic acid ethyl ester was obtained as acolorless oil (5.33 g, 92% of theory). Mass (calculated)C₁₀H₈BrFO_(3[)275.072]; (found) [M]⁺=274, [M+2-H]⁺=276.

b)(S)-(5-Bromo-2-fluoro-phenyl)-[(Z)-2-methyl-propane-2-sulfinylimino]-aceticacid ethyl ester

A solution of (S)-(−)-2-methyl-2-propanesulfinamide (2.35 g, 19.4 mmol)and (5-bromo-2-fluoro-phenyl)-oxo-acetic acid ethyl ester (5.33 g, 19.4mmol) in tetrahydrofuran (80 ml) was treated at room temperature withtitanium(IV) ethoxide (8.04 ml, 38.8 mmol). The light brown solution wasstirred at 70° C. for 3.5 hours. For the workup, the cooled reactionmixture was poured into ice water, diluted with ethyl acetate, andfiltered through a pad of Dicalite. The organic layer was separated,washed with brine, dried over sodium sulfate, and finally evaporated atreduced pressure. The crude product (6.7 g) was purified bychromatography on silica gel using a gradient of cyclohexane anddichloromethane=100/0 to 0/100 as the eluent.(S)-(5-bromo-2-fluoro-phenyl)-[(Z)-2-methyl-propane-2-sulfinylimino]-aceticacid ethyl ester was obtained as a yellow oil (4.9 g, 66% of theory).Mass (calculated) C₁₄H₁₇BrFNO₃S [378.260]; (found) [M+H]⁺=378,[M+2-H]⁺=380.

c) (S)-2-Methyl-propane-2-sulfinic acid[(R)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1,2-dimethyl-propyl]-amide

A solution of(S)-(5-bromo-2-fluoro-phenyl)-[(Z)-2-methyl-propane-2-sulfinylimino]-aceticacid ethyl ester (10.4 g, 27 mmol) in anhydrous tetrahydrofuran (150 ml)was cooled to −70° C. A solution of methyl magnesium bromide (3.2 M in2-methyl-tetrahydrofuran (30.1 ml, 96 mmol) was added dropwise. Theyellow solution was warmed up to room temperature during 2 hours andthen stirred for 16 hours. For the workup, the yellow solution wasquenched with ice-cold saturated ammonium chloride solution andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over sodium sulfate, filtered and evaporated at reducedpressure to give brown oil (11 g). The crude product was purified bychromatography on silica gel using a gradient of heptane and ethylacetate=100/0 to 20/80 as the eluent. (S)-2-Methyl-propane-2-sulfinicacid[(R)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1,2-dimethyl-propyl]-amidewas obtained as a colorless oil (4.2 g, 40% of theory). Mass(calculated) C₁₅H₂₃BrFNO₂S [380.320]; (found) [M+H]⁺=380, [M+2-H]⁺=382.

d) (R)-3-Amino-3-(5-bromo-2-fluoro-phenyl)-2-methyl-butan-2-ol

A solution of (S)-2-methyl-propane-2-sulfinic acid[(R)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1,2-dimethyl-propyl]-amide(4.2 g, 11.04 mmol) in tetrahydrofuran (200 ml) was cooled to 0° C.Hydrochloric acid (4 M in dioxane, 11 ml) was added dropwise. The icebath was removed and stirring continued for 1.5 hours at roomtemperature. For the workup, the reaction mixture was poured onto asodium carbonate solution (2 M), extracted twice with ethyl acetate,dried over sodium sulfate, and evaporated at reduced pressure, finallydried under high vacuum. The(R)-3-amino-3-(5-bromo-2-fluoro-phenyl)-2-methyl-butan-2-ol was obtainedas light yellow oil (2.94 g, 96.4% of theory). Mass (calculated)C₁₁H₁₅BrFNO [276.147]; (found) [M+H]⁺=276, [M+2-H]⁺=278.

e)N—[(R)-1-(5-Bromo-2-fluoro-phenyl)-2-hydroxy-1,2-dimethyl-propyl]-2-chloro-acetamide

A solution of(R)-3-amino-3-(5-bromo-2-fluoro-phenyl)-2-methyl-butan-2-ol (2.91 g,10.5 mmol) in dichloromethane (35 ml) was stirred intensively togetherwith a saturated sodium hydrogen-carbonate solution (30 ml) at 0° C.Chloroacetyl chloride (0.92 ml, 11.6 ml) was added and stirringcontinued for 1 hour at 0° C. For the workup, the aqueous layer wasseparated and extracted with dichloromethane. The combined organiclayers were dried over sodium sulfate, then evaporated. The titlecompound was obtained as a white solid (3.5 g, 94% of theory) which wasused in the next step without further purification. Mass (calculated)C₁₃H₁₆BrClFNO₂ [352.629]; (found) [M+H]⁺=352, [M+2-H]⁺=354.

f) (R)-5-(5-Bromo-2-fluoro-phenyl)-5,6,6-trimethyl-morpholin-3-one

A dispersion ofN—[(R)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1,2-dimethyl-propyl]-2-chloro-acetamide(2.79 g, 7.91 mmol) in toluene (80 ml) at 23° C. was treated dropwisewith a solution of potassium amylate (1.7 M in toluene, 24 ml, 41 mmol)within 30 minutes (slightly exothermic reaction). After completeaddition the mixture was stirred at 23° C. for 45 minutes. For theworkup, the reaction mixture was poured into hydrochloric acid (1M) andextracted with ethyl acetate. The organic layer was separated and washedwith a saturated sodium hydrogen-carbonate solution and brine. Thecombined aqueous layers were re-extracted twice with ethyl acetate. Thecombined organic layers were dried over sodium sulfate, then evaporatedat reduced pressure to yield light brown oil. The crude product waspurified by chromatography on silica gel using a gradient of heptane andethyl acetate as the eluent. The(R)-5-(5-bromo-2-fluoro-phenyl)-5,6,6-trimethyl-morpholin-3-one wasobtained as a light yellow gum (1.83 g, 73% of theory). Mass(calculated) C₁₃H₁₅BrFNO_(2[)316.168]; (found) [M+H]⁺=316, [M+2-H]⁺=318.

g)(R)-5-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-5,6,6-trimethyl-morpholin-3-one

In a sealed tube a solution of(R)-5-(5-bromo-2-fluoro-phenyl)-5,6,6-trimethyl-morpholin-3-one (1.0 g,3.2 mmol) in toluene (8 ml) was treated consecutively with sodiumtert-butylate (912 mg, 9.5 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl(tert-butyl-x-phos) (134 mg, 10 mol %) andtris(dibenzylideneacetone)-dipalladium chloroform complex[Pd₂(dba)₃.CHCl₃] (98 mg, 5 mol %). Benzophenone imine (1.06 ml, 6.3mmol) was added finally via syringe. The tube was sealed under argon andthe mixture was stirred at 105° C. for 20 h. For the workup, the brownsolution was extracted with ethyl acetate and water. The organic layerwas separated, washed with brine, dried over sodium sulfate, filteredand evaporated at reduced pressure to give brown oil (1.5 g). The crudeproduct was purified by chromatography on silica gel using a gradient ofheptane and ethyl acetate=100/0 to 50/50 as the eluent. The(R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5,6,6-trimethyl-morpholin-3-onewas obtained as a light yellow foam (1.13 g, 86% of theory). Mass(calculated) C₂₆H₂₅FN₂O_(2[)416.493]; (found) [M+H]⁺=417.

h) (5-Chloro-thiophene-2-carboxylic acid[3-(-5-(5-Amino-2-fluoro-phenyl)-5,6,6-trimethyl-morpholine-3-thione

The(R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5,6,6-trimethyl-morpholin-3-one(1.13 g; 2.71 mmol) was dissolved in dioxane (80 ml) and the Lawesson'sReagent (691 mg, 1.71 mmol) was added at room temperature. The reactionmixture was stirred at 80° C. for 2 hours. Thereafter, the greensolution was cooled to 23° C., then hydrochloric acid (1M, 3.42 ml) wasadded and the mixture was stirred for 30 minutes at room temperature.For the workup, the reaction mixture was poured into a saturated sodiumhydrogen-carbonate solution and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over sodium sulfate, andevaporated at reduced pressure to give blue oil (1.33 g). The crudeproduct was purified by chromatography on silica gel using a gradient ofheptane and ethyl acetate=100/0 to 50/50 as the eluent. The(R)-5-(5-amino-2-fluoro-phenyl)-5,6,6-trimethyl-morpholine-3-thione wasobtained as a white foam (0.63 g, 86% of theory). Mass (calculated)C₁₃H₁₇FN₂OS [268.354]; (found) [M+H]⁺=269.

Preparation of Building block L(R)-5-(3-Amino-phenyl)-2,2,5-trimethyl-morpholine-3-thione

a) (R)-5-(3-Bromo-phenyl)-5-methyl-morpholin-3-one

In close analogy to the reaction sequence described for the preparationof Building block A, the cyclization of the(R)—N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamidewith potassium tert-butylate yielded the title compound as a whitesolid. Mass (calculated) C₁₁H₁₂BrNO_(2[)270.125]; (found) [M+H]⁺=270,[M+2-H]⁺=272.

b) (R)-5-(3-Bromo-phenyl)-4-(4-methoxy-benzyl)-5-methyl-morpholin-3-one

A solution of(R)-5-(3-amino-phenyl)-4-(4-methoxy-benzyl)-5-methyl-morpholin-3-one(1.0 g, 3.7 mmol) in N,N-dimethylformamide was added within 5 minutes at0° C. to a solution of potassium tert-butanolate (0.636 g, 5.7 mmol).After stirring at 0° C. for 30 minutes the light yellow solution wascooled to −4° C. and treated with a solution of 4-methoxybenzylbromide(1.12 g, 5.6 mmol) in N,N-dimethylformamide (4 ml). The reaction mixturewas left to warm to room temperature, then the solvent was evaporated atreduced pressure, and the residue treated with saturated ammoniumchloride solution (50 ml) and ethyl acetate (100 ml). The organic layerwas separated, washed with brine (50 ml), dried over sodium sulfate, andevaporated at reduced pressure. The crude product was purified bychromatography on silica gel using a gradient of heptane and ethylacetate=100/0 to 50/50 as the eluent. The(R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-5-methyl-morpholin-3-one wasobtained as colorless oil (1.19 g, 83% of theory). Mass (calculated)C₁₉H₂₀BrNO_(3[)390.275]; (found) [M+H]⁺=390, [M+2-H]⁺=392.

c)(2S,5R)-5-(3-Bromo-phenyl)-4-(4-methoxy-benzyl)-2,5-dimethyl-morpholin-3-one

A dried flask was charged under an argon atmosphere with a solution of(R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-5-methyl-morpholin-3-one(600 mg, 1.5 mmol) in tetrahydrofuran (16 ml) which was cooled to −75°C. Lithium isopropylamine (1.54 ml, 3 mmol) was added, and after theaddition of diazomethane (502 mg, 3.5 mmol) the reaction was complete.For the workup, the cold reaction mixture was quenched with a saturatedammonium chloride solution (15 ml) and extracted with a mixture ofdichloromethane (40 ml) and water (15 ml). The organic layer was driedover sodium sulfate and evaporated to yield the crude(2S,5R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,5-dimethyl-morpholin-3-oneas a brownish oil which was engaged in the next step without furtherpurification. Mass (calculated) C₂₀H₂₂BrNO₃[404.307]; (found)[M+H]⁺=404, [M+2-H]⁺=406.

d)(R)-5-(3-Bromo-phenyl)-4-(4-methoxy-benzyl)-2,2,5-trimethyl-morpholin-3-one

A dried flask was charged under an argon atmosphere with a solution ofthe crude(2S,5R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,5-dimethyl-morpholin-3-one(622 mg) in tetrahydrofuran (16 ml) which was cooled to −75° C. Lithiumdiisopropylamide (1.54 ml, 3 mmol) was rapidly added, followed byiodomethane (502 mg, 3.5 mmol). After 15 minutes at −75° C. the reactionwas complete. For the workup, the cold reaction mixture was quenchedwith a saturated ammonium chloride solution (15 ml) and extracted with amixture of dichloromethane (40 ml) and water (15 ml). The organic layerwas dried over sodium sulfate and evaporated. The crude product waspurified by chromatography on silica gel using a gradient of heptane andethyl acetate=100/0 to 66/34 as the eluent. The(R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,2,5-trimethyl-morpholin-3-onewas obtained as a white solid (495 mg, 77% of theory). Mass (calculated)C₂₁H₂₄BrNO_(3[)418.334]; (found) [M+H]⁺=418, [M+2-H]⁺=420.

e) (R)-5-(3-Bromo-phenyl)-2,2,5-trimethyl-morpholin-3-one

A solution of(R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,2,5-trimethyl-morpholin-3-one(487 mg, 1.2 mmol) and anisole (2.305 g, 21.3 mmol) in trifluoroaceticacid (6 ml) was treated dropwise with trifluoromethanesulfonic acid(1.19 ml). After complete addition, the violet reaction mixture washeated at 73° C. for 23 hours. The cooled reaction mixture was pouredinto a saturated solution of sodium hydrogen-carbonate which wasextracted with ethyl acetate. The organic layer was separated, washedwith brine, dried over sodium sulfate, and evaporated at reducedpressure. The crude product was purified by chromatography on silica gelusing a gradient of heptane and ethyl acetate=100/0 to 66/34 as theeluent. The product containing fractions (550 mg, orange foam) werecollected and engaged in the next step without further purification andcharacterization.

f)(R)-5-[3-(Benzhydrylidene-amino)-phenyl]-2,2,5-trimethyl-morpholin-3-one

In analogy to step g) in the synthesis of Building block K, thepalladium-catalyzed amination of the(R)-5-(3-bromo-phenyl)-2,2,5-trimethyl-morpholin-3-one yielded the titlecompound as a yellow foam (83% of theory). Mass (calculated)C₂₆H₂₆N₂O_(2[)398.503]; (found) [M+H]⁺=399.

g)(R)-5-[3-(Benzhydrylidene-amino)-phenyl]-2,2,5-trimethyl-morpholin-3-thione

In analogy to step h) in the synthesis of Building block K, thetreatment of(R)-5-[3-(benzhydrylidene-amino)-phenyl]-2,2,5-trimethyl-morpholin-3-onewith Lawesson's reagent yielded the title compound as a yellow foamafter chromatography on silica gel using a gradient of heptane and ethylacetate=100/0 to 50/50 as the eluent (53% of theory). Mass (calculated)C₂₆H₂₆N₂OS [414.570]; (found) [M+H]⁺=415.

h) (R)-5-(3-Amino-phenyl)-2,2,5-trimethyl-morpholine-3-thione

In analogy to step h) in the synthesis of Building block K, thehydrolysis of(R)-5-[3-(benzhydrylidene-amino)-phenyl]-2,2,5-trimethyl-morpholin-3-thionewith hydrochloric acid yielded the title compound (Building block L) asan off-white solid (86% of theory). Mass (calculated) C₁₃H₁₈N₂OS[250.37]; (found) [M+H]⁺=251.

Preparation of Building block M (2R,5R)— and(2S,5S)₅-(5-Amino-2-fluoro-phenyl)-2-benzyl-5-methyl-morpholin-3-one

a)(2RS)-Bromo-N—[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-propionamide

A solution of (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol (1.5g, 6 mmol) and triethylamine (1.01 ml, 7.3 mmol) in acetonitrile (31 ml)was cooled to 0° C. A solution of (RS)-2-bromo-3-phenyl-propionylchloride (CAS 42762-86-7) (1.637 g, 6.6 mmol) in acetonitrile was addeddropwise. After complete addition the reaction mixture was left to warmto room temperature. After 1 hour the reaction mixture was evaporatedunder reduced pressure and directly purified by chromatography on silicagel using a gradient of heptane and ethyl acetate=100/0 to 50/50 as theeluent. Besides theN—[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-acrylamide(0.233 g, 10% of theory), the(2RS)-bromo-N—[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-propionamide(mixture of diastereoisomers 3:2) was obtained as a white solid (1.985g, 71.5% of theory). Mass (calculated) C₁₈H₁₈Br₂FNO_(2[)459.156];(found) [M+H]⁺=457, [M+2-H]⁺=459, [M+4-H]⁺=461.

b) (2R,5S)-2-Benzyl-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-oneand(2S,5R)-2-Benzyl-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one

In analogy to the cyclization reaction described for the preparation ofBuilding block C, the reaction of(2RS)-bromo-N—[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-propionamidewith potassium tert-butylate yielded besides theN—[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-acrylamide(0.381 g, 30% of theory),(2R,5S)-2-benzyl-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-oneand(2S,5R)-2-benzyl-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one asthe dominant diastereoisomer in form of a white foam (51% of theory).Mass (calculated) C₁₈H₁₇BrFNO_(2[)378.244]; (found) [M+H]⁺=378,[M+2-H]⁺=380.

c) (2R,5S)— and(2S,5R)-5-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-2-benzyl-5-methyl-morpholin-3-oneand (2R,5R)— and(2S,5S)-5-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-2-benzyl-5-methyl-morpholin-3-one

In analogy to step g) in the synthesis of Building block K, thepalladium-catalyzed amination of the(2R,5S)-2-benzyl-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-oneand(2S,5R)-2-benzyl-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-oneyielded the title compounds. After chromatography on silica gel using agradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent thefirst eluting (2R,5S)— and(2S,5R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-2-benzyl-5-methyl-morpholin-3-onewas obtained as a yellow foam (43% of theory). Mass(calculated)C₃₁H₂₇FN₂O_(2[)478.564]; (found) [M+H]⁺=479. The secondeluting (2R,5R)— and(2S,5S)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-2-benzyl-5-methyl-morpholin-3-onewas obtained as a light yellow foam (48% of theory). Mass (calculated)C₃₁H₂₇FN₂O_(2[)478.564]; (found) [M+H]⁺=479.

d) (2R,5R)— and(2S,5S)-5-(5-Amino-2-fluoro-phenyl)-2-benzyl-5-methyl-morpholin-3-one

A solution of (2R,5R)— and(2S,5S)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-2-benzyl-5-methyl-morpholin-3-one(359 mg, 0.8 mmol) in dioxane (6 ml) was cooled to 15° C. and treatedwith hydrochloric acid (1 N, 0.9 mmol). The reaction mixture was left towarm to room temperature and stirred for another 2 hours. For theworkup, the solution was evaporated at reduced pressure and the residuetreated with dichloromethane (20 ml) and Huenig's base (0.219 ml). Theyellow solution was extracted with water (2×10 ml). The aqueous layerwas separated, basified to pH 9 with Huenig's base and re-extracted withdichloromethane (3×10 ml). The four organic layers were combined, driedover sodium sulfate and evaporated. After chromatography on aSilicycle-Si-amine phase using a gradient of dichloromethane andmethanol=100/0 to 99/1 the (2R,5R)— and(2S,5S)-5-(5-amino-2-fluoro-phenyl)-2-benzyl-5-methyl-morpholin-3-onewas obtained as a white foam (169 mg, 72% of theory). Mass (calculated)C₁₈H₁₉FN₂O_(2[)314.363]; (found) [M+H]⁺=315.

Preparation of Building block N (2S,5R)— and(2R,5S)-5-(5-Amino-2-fluoro-phenyl)-2-benzyl-5-methyl-morpholin-3-one

In a procedure analogous to step d) in the preparation of Building blockM the acidic hydrolysis of (2R,5S)— and(2S,5R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-2-benzyl-5-methyl-morpholin-3-oneyielded the title compound as an off-white foam. Mass (calculated)C₁₈H₁₉FN₂O_(2[)314.363]; (found) [M+H]⁺=315.

Preparation of Building block 0(RS)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thionehydrochloride

In a reaction sequence analogous to that described for the preparationof the optically active Building block H, the cyclization of the(RS)—N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamidewith potassium tert-butylate, followed by the palladium-catalyzedamination yielded the(RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one.Its reaction with Lawesson's reagent and the following treatment withhydrochloric acid yielded the title compound as a light yellow solid.Mass (calculated) C₁₁H₁₃FN₂OS.ClH [276.762]; (found) [M+H]⁺=241.

Preparation of Building block P(RS)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylaminedihydrochloride

In a reaction sequence analogous to that described for the opticallyactive analogue Building block Q, the(RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholine-3-thionewas transformed into the title compound which was obtained as a lightbrown foam. Mass (calculated) C₁₁H₁₄FN₃O.2ClH [296.174]; (found)[M+H]⁺=224.

Preparation of Building block Q(R)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

A suspension of(R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholine-3-thione[Building block H, step b)] (1.25 g, 3.09 mmol) in methanol (57 ml) wastreated with a solution of ammonia in methanol (26.5 ml, 185 mmol) and asolution of tert-butyl-hydroperoxide (4.28 ml, 30.9 mmol). Afterstiffing at room temperature for 40 hours, the reaction mixture wasdiluted with water and extracted three times with dichloromethane. Thecombined organic layers were washed with water, dried over sodiumsulfate, evaporated, and dried at high vacuum at room temperature toyield the crude(R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamineas a light brown foam which was dissolved in dioxane (20 ml) and treatedwith hydrochloric acid (1 M, 3.09 ml). After 40 minutes at roomtemperature the reaction mixtures was diluted with a saturated solutionof hydrogen-carbonate and water. The mixture was extracted three timeswith ethyl acetate, then the aqueous phase basified with a solution ofsodium hydroxide (28%). After four extractions with dichloromethane, theorganic layers were combined, dried over sodium sulfate and evaporated.The(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylaminewas obtained as an off-white waxy solid (445 mg, 64% of theory).

Preparation of Building block R(2R,5R)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-2-phenyl-morpholin-3-onehydrochloride

a) (R)-2-(5-bromo-2-fluoro-phenyl)-2-(4-methoxy-benzylamino)-propan-1-ol

A solution of (R)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol (5.0g, 20.2 mmol) and 4-methoxybenzaldehyde (2.8 g, 20.2 mmol) in1,2-dichloroethane (150 ml) was treated with sodiumtriacetoxyborohydride (8.81 g, 40.3 mmol) at room temperature. TLC check(eluent: heptane:ethyl acetate=1:1) showed complete reaction after 30minutes. For the workup, to the reaction mixture was added ethyl acetate(250 ml) and saturated sodium hydrogen-carbonate solution (100 ml). Theaqueous layer was separated, and then extracted with ethyl acetate (250ml). The combined organic layers were washed with saturated sodiumchloride solution (100 ml), thereafter dried over sodium sulfate andevaporated at reduced pressure. After chromatography onSilicycle-Si-amine column using a gradient of heptane and ethylacetate=100/0 to 50/50 as the eluent,(R)-2-(5-bromo-2-fluoro-phenyl)-2-(4-methoxy-benzylamino)-propan-1-olwas obtained as a colorless oil (7.29 g, 98% of theory). Mass(calculated) C₁₇H₁₉BrFNO_(2[)368.25]; (found) [M+H]⁺=368, [M+2-H]⁺=370.

b)[(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-(4-methoxy-benzyl)-amine

A solution of(R)-2-(5-bromo-2-fluoro-phenyl)-2-(4-methoxy-benzylamino)-propan-1-ol(6.95 g, 18.9 mmol) in dichloromethane (170 ml) was treated at roomtemperature with triethylamine (5.78 ml, 41.5 mmol),4-dimethylaminopyridine (1.15 g, 9.43 mmol), andtert-butyldimethylchlorosilane (1.15 g, 37.7 mmol). After 16 hours atroom temperature the reaction mixture was consecutively extracted withsaturated sodium hydrogen-carbonate solution (100 ml), water (100 ml),and brine (100 ml). The aqueous layers were re-extracted withdichloromethane (100 ml). The combined organic layers were dried oversodium sulfate and evaporated at reduced pressure. After chromatographyon Silicycle-Si-amine column using heptane as the eluent,[(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-(4-methoxy-benzyl)-aminewas obtained as a colorless oil (8.0 g, 88% of theory). Mass(calculated) C₂₃H₃₃BrFNO₂Si [482.51]; (found) [M+H]⁺=482, [M+2-H]⁺=484.

c)(RS)—N—[(R)-1-(5-Bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-2-chloro-N-(4-methoxy-benzyl)-2-phenyl-acetamide

A solution of[(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-(4-methoxy-benzyl)-amine(1.035 g, 2.15 mmol) in acetonitrile (16 ml) was treated withtriethylamine (0.36 ml, 2.57 mmol). The mixture was cooled to 10° C. anda solution of (RS)-2-chloro-2-phenyl-acetyl chloride (0.34 ml, 2.36mmol) in acetonitrile (2 ml) was added slowly. The reaction mixture wasallowed to warm to room temperature and was stirred for 3 hours. Becausethe transformation was not complete, triethylamine (0.33 ml, 2.36 mmol)was again added, the reaction mixture cooled to −5° C., then treatedwith a solution of (RS)-2-chloro-2-phenyl-acetyl chloride (0.31 ml, 2.15mmol) in acetonitrile (1 ml). The reaction mixture was allowed to warmto room temperature and was stirred for 22 hours. Thereafter, themixture was evaporated at reduced pressure and without further workupdirectly purified by chromatography on Silicycle-Si-amine column using agradient of heptane and ethyl acetate=100/0 to 70/30 as the eluent.(RS)—N—[(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-2-chloro-N-(4-methoxy-benzyl)-2-phenyl-acetamidewas obtained as a white foam (1.068 g, 78% of theory). Mass (calculated)C₃₁H₃₈BrClFNO_(3[)635.09]; (found) [M+H]⁺=638, [M+2-H]⁺=636,[M+4-H]⁺=634.

d)(2RS,5R)-5-(5-Bromo-2-fluoro-phenyl)-4-(4-methoxy-benzyl)-5-methyl-2-phenyl-morpholin-3-one

A solution of(RS)—N—[(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-2-chloro-N-(4-methoxy-benzyl)-2-phenyl-acetamide(1.068 g, 1.68 mmol) in tetrahydrofuran (30 ml) was cooled to 0° C. andtreated dropwise during 10 minutes with a solution of tetrabutylammoniumfluoride (1 M, 3.36 mmol) in tetrahydrofuran. The orange-coloredreaction mixture was stirred at 0° C. for 5 minutes, then for 4 hours atroom temperature. For the workup, the reaction mixture was evaporated atreduced pressure, the residue partitioned between water (10 ml) andethyl acetate (25 ml) and stirred for 15 minutes. The layers wereseparated and the aqueous layer re-extracted with ethyl acetate (25 ml).The combined organic layers were dried over sodium sulfate andevaporated at reduced pressure. After chromatography on aSilicycle-Si-amine column using a gradient of heptane and ethylacetate=100/0 to 50/50 as the eluent, the(2RS,5R)-5-(5-bromo-2-fluoro-phenyl)-4-(4-methoxy-benzyl)-5-methyl-2-phenyl-morpholin-3-onewas obtained as a white foam (369 mg, 45% of theory). Mass (calculated)C₂₅H₂₃BrFNO_(3[)484.37]; (found) [M+H]⁺=484, [M+2-H]⁺=486.

e)(2RS,5R)-5-(5-Bromo-2-fluoro-phenyl)-5-methyl-2-phenyl-morpholin-3-one

In a manner analogous to that described for the preparation of buildingblack L d) the cleavage of the 4-methoxybenzyl group withtrifluoromethanesulfonic acid yielded the title compound as the maincomponent after flash chromatography on silica gel using a gradient ofheptane and ethyl acetate=100/0 to 35/65 as the eluent. Mass(calculated) C₁₇H₁₅BrFNO₂[364.22]; (found) [M+H]⁺=364, [M+2-H]⁺=366. Thecrude material was engaged in the next step without furtherpurification.

f)(2R,5R)-5-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-2-phenyl-morpholin-3-oneand(2S,5R)-5-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-2-phenyl-morpholin-3-one

In analogy to step g) in the synthesis of Building block K, thepalladium-catalyzed amination of the(2RS,5R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-2-phenyl-morpholin-3-oneproduced the diastereomeric mixture of the imines which was separated bychromatography on silica gel using a gradient of heptane and ethylacetate=100/0 to 50/50 as the eluent yielding the(2R,5R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-2-phenyl-morpholin-3-oneas the first eluting diastereoisomer (35% of theory) and the(2S,5R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-2-phenyl-morpholin-3-oneas the second eluting diastereoisomer (40% of theory) both as a yellowfoam. Mass (calculated) C₃₀H₂₅FN₂O_(2[)464.54]; (found) [M+H]⁺=465.

g) (2R,5R)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-2-phenyl-morpholin-3-onehydrochloride

In a procedure analogous to step d) in the preparation of Building blockM the acidic hydrolysis of(2R,5R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-2-phenyl-morpholin-3-oneyielded the title compound as an off-white solid (58% of theory). Mass(calculated) C₁₇H₁₇FN₂O₂.HCl[336.80]; (found) [M+H]⁺=301.

Preparation of Building block S(2S,5R)-5-(5-Amino-2-fluoro-phenyl)-5-methyl-2-phenyl-morpholin-3-oneHydrochloride

In a procedure analogous to step d) in the preparation of Building blockM the acidic hydrolysis of(2S,5R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-2-phenyl-morpholin-3-oneyielded the title compound as a red solid (80% of theory). Mass(calculated) C₁₇H₁₇FN₂O₂.HCl[336.80]; (found) [M+H]⁺=301.

Example 1 (Method A) (RS)-3,5-Difluoro-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=3,5-Difluoro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide)a) (RS)-3,5-Difluoro-pyridine-2-carboxylic acid[3-(3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide(=3,5-Difluoro-pyridine-2-carboxylic acid[3-((RS)-3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide)

A solution of (RS)-3,5-difluoropyridin-2-carboxylic acid (0.186 g, 1.2mmol) in N,N-dimethylformamide (7 ml) was cooled to 0° C. Consecutively,1-hydroxybenzotriazole hydrate (0.199 g, 1.5 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(0.547 g, 1.4 mmol), (RS)-5-(3-amino-phenyl)-5-methyl-morpholin-3-onehydrochloride (0.250 g, 1.0 mmol), and N-ethyldiisopropylamine (0.466 g,3.6 mmol) were added, and the mixture was stirred at 0° C. for 10minutes, then left at room temperature for 16 hours. For the workup, thereaction mixture was evaporated to dryness and the residue directlypurified by chromatography on an Isolute flash NH₂ column using agradient of heptane/ethyl acetate=100/0 to 33/66 as the eluent. Therewere obtained 0.39 g (86% of theory) of(RS)-3,5-difluoro-pyridine-2-carboxylic acid[3-(3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide(=3,5-difluoro-pyridine-2-carboxylic acid[3-((RS)-3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide) as a white solid.Mass (calculated) C₁₇H₁₅F₂N₃O_(3[)347.324]; (found) [M+H]⁺=348.

b) (RS)-3,5-Difluoro-pyridine-2-carboxylic acid[3-(5-ethoxy-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=3,5-Difluoro-pyridine-2-carboxylic acid[3-((RS)-5-ethoxy-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]amide)

In a dried flask, a dispersion of(RS)-3,5-difluoro-pyridine-2-carboxylic acid[3-(3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide (0.305 g, 0.9 mmol) indichloromethane (80 ml) was treated with triethyloxoniumtetrafluoroborate (0.172 g, 0.9 mmol) under argon at room temperatureduring 16 hours. For the workup, the reaction mixture was extracted witha saturated solution of sodium hydrogen-carbonate (40 ml), the organiclayer separated and dried over sodium sulfate. After evaporation, amixture of (RS)-3,5-difluoro-pyridine-2-carboxylic acid[3-(5-ethoxy-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide and(RS)-3,5-difluoro-pyridine-2-carboxylic acid[3-(3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide(=3,5-difluoro-pyridine-2-carboxylic acid[3-((RS)-3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide) (25%) wasobtained as a light yellow foam (0.356 g). The crude product was engagedin the next step without further purification.

c) (RS)-3,5-Difluoro-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=3,5-Difluoro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide)

A dried pressure tube was charged under an argon atmosphere with adispersion of (RS)-3,5-difluoro-pyridine-2-carboxylic acid[3-(5-ethoxy-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(0.348 g, 0.9 mmol) and ammonium chloride (0.182 g, 3.4 mmol) inmethanol (10 ml). The sealed pressure tube was heated at 100° C. for 16hours. After cooling, the reaction mixture was evaporated to dryness anddirectly purified by chromatography on an Isolute flash NH₂ column usinga gradient of dichloromethane/methanol=100/0 to 95/5 as the eluent.There were obtained 0.076 g (38% of theory) of(RS)-3,5-difluoro-pyridine-2-carboxylic acid[3-(3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide(=3,5-difluoro-pyridine-2-carboxylic acid[3-((RS)-3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide) as a white solid;mass (calculated) C₁₇H₁₅F₂N₃O_(3 [)347.324]; (found) [M+H]⁺=348, and0.113 g (57% of theory) of (RS)-3,5-difluoro-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide (1)as a light yellow foam; mass (calculated) C₁₇H₁₆F₂N₄O_(2[)346.340];(found) [M+H]⁺=347.

Examples 2-17

In a reaction sequence analogous to that described in Example 1 (methodA), the following compounds were obtained starting from the condensationof the corresponding acid with Building block A,(RS)-5-(3-amino-phenyl)-5-methyl-morpholin-3-one hydrochloride, followedby the treatment with triethyloxonium tetrafluoroborate ortrimethyloxonium tetrafluoroborate and ammonium chloride:

Example 2

With 3,5-dichloro-pyridine-2-carboxylic acid the(RS)-3,5-dichloro-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=3,5-dichloro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide)(2) as a light yellow foam; (calculated) C₁₇H₁₆Cl₂N₄O_(2[)379.245];(found) [M+H]⁺=379, [M+2-H]⁺=381;

Example 3

With 4-chloro-2-fluoro-benzoic acid the(RS)—N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-chloro-2-fluoro-benzamide(3) as a white foam; (calculated) C₁₈H₁₇ClFN₃O_(2[)361.802]; (found)[M+H]⁺=362;

Example 4

With 2,4-dichloro-benzoic acid the(RS)—N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,4-dichloro-benzamide(4) as a white solid; (calculated) C₁₈H₁₇Cl₂N₃O_(2[)378.257]; (found)[M+H]⁺=378, [M+2-H]⁺=380;

Example 5

With 2,5-difluoro-benzoic acid the(RS)—N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,5-difluoro-benzamide(5) as a white foam; (calculated) C₁₈H₁₇F₂N₃O_(2[)345.347]; (found)[M+H]⁺=346;

Example 6

With 3-chloro-benzoic acid the(RS)—N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-3-chloro-benzamide(6) as a white foam; (calculated) C₁₈H₁₈ClN₃O₂[343.820]; (found)[M+H]⁺=344, [M+2-H]⁺=346;

Example 7

With 5-chloro-pyridine 2-carboxylic acid the(RS)-5-chloro-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=5-chloro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide)(7) as a white foam; (calculated) C₁₇H₁₇ClN₄O_(2[)344.804]; (found)[M+H]⁺=345;

Example 8

With 5-chloro-thiophene-2-carboxylic acid the(RS)-5-chloro-thiophene-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=5-chloro-thiophene-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide)(8) as a light yellow solid; (calculated) C₁₆H₁₆ClN₃O₂S [349.842];(found) [M+H]⁺=350;

Example 9

With 2,5-dimethyl-thiophene-3-carboxylic acid the(RS)-2,5-dimethyl-thiophene-3-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=2,5-dimethyl-thiophene-3-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide)(9) as a white solid; (calculated) C₁₈H₂₁N₃O₂S [343.449]; (found)[M+H]⁺=344;

Example 10

With 2-methyl-thiazole-4-carboxylic acid the(RS)-2-methyl-thiazole-4-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=2-methyl-thiazole-4-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide)(10) as a light yellow solid; (calculated) C₁₆H₁₈N₄O₂S [330.41]; (found)[M+H]⁺=331;

Example 11

With 2,5-dimethyl-1,3-oxazole-4-carboxylic acid the(RS)-2,5-dimethyl-oxazole-4-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=2,5-dimethyl-oxazole-4-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide)(11) as a white foam; (calculated) C₁₇H₂₀N₄O_(3[)328.37]; (found)[M+H]⁺=329;

Example 12

With 2-methyl-1,3-oxazole-4-carboxylic acid the(RS)-2-methyl-oxazole-4-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=2-methyl-oxazole-4-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide)(12) as a light yellow solid; (calculated) C₁₆H₁₈N₄O_(3[)314.34];(found) [M+H]⁺=315;

Example 13

With 2,5-dimethylfuran-3-carboxylic acid the(RS)-2,5-dimethylfuran-3-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=2,5-dimethylfuran-3-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide)(13) as a white soli; (calculated) C₁₈H₂₁N₃O_(3[)327.38]; (found)[M+H]⁺=328;

Example 14

With 1-(2,2,2-trifluoro-ethyl)-1H-pyrazole-3-carboxylic acid the(RS)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazole-3-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=1-(2,2,2-trifluoro-ethyl)-1H-pyrazole-3-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide)(14) as a white foam; (calculated) C₁₇H₁₈F₃N₅O_(2[)381.36]; (found)[M+H]⁺=382;

Example 15

With 1-methyl-1H-indazole-3-carboxylic acid the(RS)-1-methyl-1H-indazole-3-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=1-methyl-1H-indazole-3-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide)(15) as a white foam; (calculated) C₂₀H₂₁N₅O_(2[)363.42]; (found)[M+H]⁺=364;

Example 16

With pyrazolo[1,5-a]pyridine-2-carboxylic acid the(RS)-Pyrazolo[1,5-a]pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=Pyrazolo[1,5-a]pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-O-phenyl]-amide)(16) as a white solid; (calculated) C₁₉H₁₉N₅O_(2[)349.392]; (found)[M+H]⁺=350;

Example 17

With 4-chloro-2-iodo-benzoic acid the(RS)—N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-chloro-2-iodo-benzamide(17) as a light yellow solid; (calculated) C₁₈H₁₇ClIN₃O_(2[)469.713];(found) [M+H]⁺=470;

Example 18

In a reaction sequence analogous to that described in Example 1 (methodA), the following compound was obtained starting from the condensationof the corresponding acid with Building block B,(R)-5-(3-amino-phenyl)-5-methyl-morpholin-3-one hydrochloride, followedby the treatment with triethyloxonium tetrafluoroborate ortrimethyloxonium tetrafluoroborate and ammonium chloride:

With 5-chloro-pyridine 2-carboxylic acid the(R)-5-chloro-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(=5-chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide)(18) as a white foam; (calculated) C₁₇H₁₇ClN₄O_(2[)344.804]; (found)[M+H]⁺=345;

Examples 19-20

In a reaction sequence analogous to that described in Example 1 (methodA), the following compounds were obtained starting from the condensationof the corresponding acid with Building block C,(RS)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholin-3-one hydrochloride,followed by the treatment with triethyloxonium tetrafluoroborate ortrimethyloxonium tetrafluoroborate and ammonium chloride:

Example 19

With 4-chloro-benzoic acid the(RS)—N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-benzamide(19) as a light yellow solid; (calculated) C₁₈H₁₇ClFN₃O_(2[)361.802];(found) [M+I-1]⁺=362;

Example 20

With 5-chloro-pyridine 2-carboxylic acid the(RS)-5-chloro-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(=5-chloro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide)(20) as a light yellow solid; (calculated) C₁₇H₁₆ClFN₄O_(2[)362.794];(found) [M+H]⁺=363;

Example 21

In a reaction sequence analogous to that described in Example 1 (methodA), the following compound was obtained starting from the condensationof the corresponding acid with Building block D,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholin-3-one hydrochloride,followed by the treatment with triethyloxonium tetrafluoroborate ortrimethyloxonium tetrafluoroborate and ammonium chloride:

With 5-chloro-pyridine 2-carboxylic acid the(R)-5-chloro-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(=5-chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide)(21) as a white foam solid; (calculated) C₁₇H₁₆ClFN₄O_(2[)362.794];(found) [M+H]⁺=363;

Example 22 (Method B) (RS)-5-Chloro-pyridine-2-carboxylic acid[3-(5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(=5-Chloro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide)(22)

a) (RS)-5-Chloro-pyridine-2-carboxylic acid[3-(3-cyclopropyl-5-thioxo-morpholin-3-yl)-4-fluoro-phenyl]-amide(=5-Chloro-pyridine-2-carboxylic acid[3-((RS)-3-cyclopropyl-5-thioxo-morpholin-3-yl)-4-fluoro-phenyl]-amide)

A solution of 5-chloro-pyridine-2-carboxylic acid (0.136 g, 0.86 mmol)in dichloromethane (15 ml), was treated with Huenig's base (0.30 ml,1.73 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (0.328 g, 0.86 mmol) at room temperature.After 15 minutes of stirring,(RS)-5-(5-amino-2-fluoro-phenyl)-5-cyclopropyl-morpholine-3-thione(0.177 g, 0.66 mmol) was added and stirring continued for one hour. Forthe workup, the light yellow solution was poured on an ice-coldsaturated solution of sodium hydrogen-carbonate, then extracted twicewith dichloromethane. The combined organic layers were washed withbrine, dried over sodium sulfate, filtered and evaporated. The residuewas purified by chromatography on silica gel using a 9:1-mixture ofdichloromethane and ethyl acetate as the eluent. The5-Chloro-pyridine-2-carboxylic acid[3-((RS)-3-cyclopropyl-5-thioxo-morpholin-3-yl)-4-fluoro-phenyl]-amidewas obtained as an off-white solid (0.245 g, 90% of theory). Mass(calculated) C₁₉H₁₇ClFN₃O₂S [405.879]; (found) [M+H]⁺=406.

b) (RS)-5-Chloro-pyridine-2-carboxylic acid[3-5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(=5-Chloro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]amide)(22)

A solution of ammonia in methanol (7 M) (5.1 ml, 35 mmol) was added to asuspension of (RS)-5-chloro-pyridine-2-carboxylic acid[3-(3-cyclopropyl-5-thioxo-morpholin-3-yl)-4-fluoro-phenyl]-amide(=5-chloro-pyridine-2-carboxylic acid[3-((RS)-3-cyclopropyl-5-thioxo-morpholin-3-yl)-4-fluoro-phenyl]-amide)(0.240 g, 0.59 mmol) in methanol (18 ml). Thereafter, tert-butylhydroperoxide (70% in water) (0.81 ml, 5.9 mmol) was added at roomtemperature and the mixture stirred for 16 hours. For the workup, theclear solution was evaporated at reduced pressure. The residue waspurified by chromatography on silica gel using a 80:10:1-mixture ofethyl acetate, methanol, and ammonium hydroxide as the eluent. The purefractions were combined and evaporated, then the residue was treatedwith a mixture of dichloromethane and water. After evaporation of theorganic layer, the 5-chloro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(22) was obtained as a white solid (99 mg, 43% of theory). Mass(calculated) C₁₉H₁₈ClFN₄O₂S [388.828]; (found) [M+H]⁺=389.

Example 23 (RS)-5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-(5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(=5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide)(23)

In an analogous manner to that described in example 6 (Method B), thecondensation of 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid(CAS 881409-53-6) and(RS)-5-(5-amino-2-fluoro-phenyl)-5-cyclopropyl-morpholine-3-thionefollowed by the treatment with tert-butyl hydroperoxide and ammoniayielded the title compound (23) as a white solid. Mass (calculated)C₂₁H₂₀F₄N₄O_(3[)452.406]; (found) [M+H]⁺=453.

Example 24 (RS)-5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride (=5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride) a) (RS)-5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylicacid [3-(3-methyl-5-thioxo-morpholin-3-yl)-phenyl]-amide(=5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-((RS)-3-methyl-5-thioxo-morpholin-3-yl)-phenyl]-amide)

In a reaction analogous to that described in example 6 (method B), thecondensation of 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid(CAS 881409-53-6) with Building block F,(RS)-5-(3-amino-phenyl)-5-methyl-morpholine-3-thione, yielded the titlecompound as a as light yellow oil (64% of theory). Mass (calculated)C₁₉H₁₈F₃N₃O₃S [425.43]; (found) [M+H]⁺=426.

b) (RS)-5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride (=5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride)

In a pressure tube, 7 M ammonia in methanol (3.0 ml) was added to(RS)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-(3-methyl-5-thioxo-morpholin-3-yl)-phenyl]-amide (0.22 g, 0.69 mmol)and the reaction mixture was heated at 100° C. for 3 hours. UPLCanalysis showed a 1:1 conversion to the desired product. The solvent wasremoved at reduced pressure and the crude mixture was taken up with 7 Mammonia in methanol (3.0 mL). The reaction mixture was heated at 100° C.in a pressure tube for 4 hours more. UPLC analysis showed an increase inconversion to the desired product while the formation of(RS)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-(3-methyl-5-oxo-morpholin-3-yl)-phenyl]amide was also observed. Thereaction was stopped and the solvent removed at reduced pressure. Thecrude product was passed on a 2 g SCX column to yield 0.09 g of thetitle compound (24) that was further purified by preparative HPLC (20min elution) to give 0.042 g (14% of theory) of the5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride as a white foam. Mass (calculated)C₁₉H₁₉F₃N₄O_(3[)408.38]; (found) [M+H]⁺=409;

Example 25 (RS)-Pyrazine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl) phenyl]-amidehydrochloride (=Pyrazine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)phenyl]-amidehydrochloride)

The reaction analogous to that described in example 6 (method B),starting from the condensation of pyrazine-2-carboxylic acid withBuilding block F, (RS)-5-(3-amino-phenyl)-5-methyl-morpholine-3-thione,followed by the treatment with ammonia in methanol as described inexample 24, yielded the title compound (25) as a white solid. Mass(calculated) C₁₆H₁₇N₅O₂[311.35]; (found) [M+H]⁺=312;

Example 26(RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2,2,3,3,3-pentafluoro-propionamide(26)

a)(RS)-2,2,3,3,3-Pentafluoro-N-[4-fluoro-3-(3-methyl-5-oxo-morpholin-3-yl)-phenyl]-propionamide

A dispersion of(RS)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholin-3-one hydrochloride(Building block C) (0.20 g, 0.8 mmol) in dichloromethane (4.5 ml) wastreated with triethylamine (0.37 ml, 2.7 mmol), then the reactionmixture was cooled to 0° C., and, thereafter, a solution of2,2,3,3,3-pentofluoropropionic acid anhydride (0.267 g, 0.9 mmol) indichloromethane (0.5 ml) was added. The reaction mixture was stirred atroom temperature for 2 days. For the workup, the solvent was evaporatedand the crude product directly chromatographed on an Isolute flash NH₂column using a gradient of dichloromethane/methanol=100/0 to 95/5 as theeluent. There were obtained 0.21 g (74% of theory) of the title compoundas a white solid. Mass (calculated) C₁₄H₁₂F₆N₂O_(3[)370.254]; (found)[M+H]⁺=371.

b)(RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2,2,3,3,3-pentafluoro-propionamide

In a reaction sequence analogous to that described in Example 1 (methodA), the treatment of(RS)-2,2,3,3,3-pentafluoro-N-[4-fluoro-3-(3-methyl-5-oxo-morpholin-3-yl)-phenyl]-propionamidewith trimethyloxonium tetrafluoroborate and ammonium chloride yieldedthe(RS)—N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2,2,3,3,3-pentafluoro-propionamide(26) as a light yellow solid. Mass (calculated) C₁₄H₁₃F₆N₃O₂[369.269];(found) [M+H]⁺=370.

Example 27(RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-thiobenzamide(27)

A solution of(RS)—N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-benzamide(0.056 g, 0.2 mmol) in 1,2-dimethoxyethane (2 ml) was treated withLawesson's reagent (0.083 g, 0.2 mmol). After heating to 70° C. thedispersion turned into solution; the temperature was kept during 16hours. Another 0.5 eq of Lawesson's reagent were added to complete thereaction and heating was continued at 80° C. After 2 days the reactionwas still incomplete. For the workup, the reaction mixture wasevaporated to dryness and the residue directly purified bychromatography on an Isolute flash NH₂ column using a gradient ofdichloromethane/methanol=100/0 to 90/10 as the eluent. There wereobtained 0.006 g (10% of theory) of(RS)—N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-thiobenzamide(27) as a yellow solid. Mass (calculated) C₁₈H₁₇ClFN₃OS [377.87];(found) [M+H]⁺=378.

Example 28 5-Chloro-pyridine-2-carboxylic acid [3-((3R,6R)— and(3S,6)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

In a reaction sequence analogous to that described in Example 1 (methodA), the title compound was obtained starting from the condensation of5-chloro-pyridine-2-carboxylic acid with Building block M, (2R,5R)— and(2S,5S)-5-(5-amino-2-fluoro-phenyl)-2-benzyl-5-methyl-morpholin-3-one,followed by the treatment with trimethyloxonium tetrafluoroborate andammonium chloride as a light yellow foam. Mass (calculated)C₂₄H₂₂ClFN₄O_(2[)452.915]; (found) [M+H]⁺=453.

Example 29 5-Chloro-pyridine-2-carboxylic acid [3-((3R,6S)— and(3S,6R)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

In a reaction sequence analogous to that described in Example 1 (methodA), the title compound was obtained starting from the condensation of5-chloro-pyridine-2-carboxylic acid with Building block N, (2S,5R)— and(2R,5S)-5-(5-amino-2-fluoro-phenyl)-2-benzyl-5-methyl-morpholin-3-one,followed by the treatment with trimethyloxonium tetrafluoroborate andammonium chloride as a light yellow foam. Mass (calculated)C₂₄H₂₂ClFN₄O_(2[)452.915]; (found) [M+H]⁺=453.

Examples 30 and 31 5-Chloro-pyridine-2-carboxylic acid[3-((3R,6R)-5-amino-3-methyl-6-phenyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideand 5-Chloro-pyridine-2-carboxylic acid[3-((3R,6S)-5-amino-3-methyl-6-phenyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

In a reaction sequence analogous to that described in Example 1 (methodA), the title compounds were obtained starting from the condensation of5-chloro-pyridine-2-carboxylic acid with Building block S,(2S,5R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-2-phenyl-morpholin-3-onehydrochloride, to yield the 5-chloro-pyridine-2-carboxylic acid[4-fluoro-3-((3R,6S)-5-methoxy-3-methyl-6-phenyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide.Treatment with trimethyloxonium tetrafluoroborate and ammonium chlorideresulted in an epimerized mixture of 5-chloro-pyridine-2-carboxylic acid[3-((3R,6R)-5-amino-3-methyl-6-phenyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideand 5-chloro-pyridine-2-carboxylic acid[3-((3R,6S)-5-amino-3-methyl-6-phenyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidewhich was separated by chromatography on a Si-amine column using agradient of dichloromethane and methanol=100/0 to 97/3 as the eluent.Both epimers were obtained as off-white powders. Mass (calculated)C₂₃H₂₀ClFN₄O_(2[)438.89]; (found) [M+H]⁺=439.

Examples 32-52

In a reaction sequence analogous to that described in example 22 (methodB), the condensation of carboxylic acids with Building blocks F, H, K, Land O followed by the treatment of the resulting thiones with a mixtureof ammonia in water and tert-butyl hydroperoxide yielded the followingcompounds:

Example 32

With 5-butyl-pyridine-2-carboxylic acid and Building block F,(RS)-5-(3-amino-phenyl)-5-methyl-morpholine-3-thione, the5-butyl-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride (32) (yield: 8% of theory). Mass (calculated)C₂₁H₂₆N₄O₂.HCl[402.923]; (found) [M+H]⁺=367.

Example 33

With 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid and Buildingblock F, (RS)-5-(3-amino-phenyl)-5-methyl-morpholine-3-thione, the3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(33) (yield: 50% of theory). Mass (calculated)C₁₈H₁₆ClF₃N₄O₂.HCl[449.258]; (found) [M+H]⁺=413.

Example 34

With 3,5-dichloro-pyridine-2-carboxylic acid and Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the3,5-dichloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(34) as a white solid. Mass (calculated) C₁₇H₁₅Cl₂FN₄O_(2[)397.235];(found) [M+H]⁺=397, [M+2-H]⁺=399.

Example 35

With 5-chloro-pyrimidine-2-carboxylic acid and Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the5-chloro-pyrimidine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(35) as a white solid. Mass (calculated) C₁₆H₁₅ClFN₅O_(2[)363.778];(found) [M+H]⁺=364.

Example 36

With 5-trifluoromethyl-furan-3-carboxylic acid and Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the5-trifluoromethyl-furan-3-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(36) as a white solid. Mass (calculated) C₁₇H₁₅F₄N₃O_(3[)385.315];(found) [M+H]⁺=386.

Example 37

With 3-fluoro-pyridine-2-carboxylic acid and Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the3-fluoro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(37) as a white foam. Mass (calculated) C₁₇H₁₆F₂N₄O_(2[)346.335];(found) [M+H]⁺=347.

Example 38

With 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid and Buildingblock H, (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione,the 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(38) as a yellow foam. Mass (calculated) C₁₈H₁₅ClF₄N₄O_(2[)430.787];(found) [M+H]⁺=431.

Example 39

With 2-methyl-oxazole-4-carboxylic acid and Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the2-methyl-oxazole-4-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(39) as an off-white foam. Mass (calculated) C₁₆H₁₇FN₄O_(3[)323.333];(found) [M+H]⁺=333.

Example 40

With 1-difluoromethyl-1H-pyrazole-3-carboxylic acid and Building blockH, (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the1-difluoromethyl-1H-pyrazole-3-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(40) as a white foam. Mass (calculated) C₁₆H₁₆F₃N₅O_(2[)367.329];(found) [M+H]⁺=368.

Example 41

With 3,5-difluoro-pyridine-2-carboxylic acid and Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the3,5-difluoro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(41) as an off-white solid. Mass (calculated) C₁₇H₁₅F₃N₄O_(2[)364.325];(found) [M+H]⁺=365.

Example 42

With 4-cyano-2-fluoro-benzoic acid and Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, theN-[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-cyano-2-fluoro-benzamide(42) as a white solid. Mass (calculated) C₁₉H₁₆F₂N₄O_(2[)370.357];(found) [M+H]⁺=371.

Example 43

With 4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid and Building blockH, (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(43) as a white solid. Mass (calculated) C₁₆H₁₇ClFN₅O_(2[)365.794];(found) [M+H]⁺=366.

Example 44

With 3-methyl-thiophene-2-carboxylic acid and Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the3-methyl-thiophene-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(44) as a white foam. Mass (calculated) C₁₇H₁₈FN₃O₂S [347.412]; (found)[M+H]⁺=348.

Example 45

With 5-phenyl-oxazole-4-carboxylic acid and Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the5-phenyl-oxazole-4-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(45) as a white solid. Mass (calculated) C₂₁H₁₉FN₄O_(3[)394.404];(found) [M+H]⁺=395.

Example 46

With 3-chloro-thiophene-2-carboxylic acid and Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the3-chloro-thiophene-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(46) as a white foam. Mass (calculated) C₁₆H₁₅ClFN₃O₂S [367.830];(found) [M+H]⁺=368.

Example 47

With 2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid and Buildingblock H, (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione,the 2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(47) as a white foam. Mass (calculated) C₁₇H₁₆F₄N₄O₂S [416.397]; (found)[M+H]⁺=417.

Example 48

With 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid and Buildingblock H, (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione,the 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(48) as a colorless solid. Mass (calculated) C₁₉H₁₈F₄N₄O_(3[)426.360];(found) [M+H]⁺=427.

The 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid was preparedas follows:

a) To a solution of 3-hydroxy-pyridine-2-carboxylic acid methyl ester(200 mg, 1.3 mmol) in N,N-dimethylformamide (2.0 ml) was added at 22° C.sodium hydride (55% in oil, 64 mg) and stirring was continued until gasevolution ceased. The suspension was cooled to 0° C. and treated withtrifluoroethyl trifluoromethanesulfonate (728 mg) and stirring wascontinued at 22° C. for 2 hours. The mixture was partitioned betweensaturated sodium hydrogen-carbonate solution and ethyl acetate, and theorganic layer was dried and evaporated. The residue was purified bychromatography on silica using n-heptane and ethyl acetate (3:1) as theeluent to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acidmethyl ester as a pale green oil. Mass (calculated)C₉H₈F₃NO_(3[)235.16]; (found) [M+H]⁺=236.b) A solution of 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acidmethyl ester (216 mg, 0.9 mmol) in methanol (1 ml) was treated with asolution of lithium hydroxide (78 mg, 3.3 mmol) in water (0.1 ml) andstirring was continued at 22° C. for 2 hours. The solution wasevaporated and the residue triturated with 1N aqueous hydrochloric acid.The suspension was filtered, the residue washed with water and dried togive 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid as acolorless solid. Mass (calculated) C₈H₆F₃NO_(3[)221.14]; (found)[M−H]⁻=220.

Example 49

With 5-chloro-pyridine-2-carboxylic acid and Building block K,(R)-5-(5-amino-2-fluoro-phenyl)-5,6,6-trimethyl-morpholine-3-thione, the5-chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(49) as a light yellow foam. Mass (calculated)C₁₉H₂₀ClFN₄O_(2[)390.844]; (found) [M+H]⁺=391.

Example 50

With 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid and Buildingblock K,(R)-5-(5-amino-2-fluoro-phenyl)-5,6,6-trimethyl-morpholine-3-thione, the5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(50) as a white solid. Mass (calculated) C₂₁H₂₂F₄N₄O_(3[)454.422];(found) [M+H]⁺=455.

Example 51

With 5-chloro-pyridine-2-carboxylic acid and Building block L,(R)-5-(3-amino-phenyl)-2,2,5-trimethyl-morpholine-3-thione the5-chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3,6,6-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(51) as a white solid. Mass (calculated) C₁₉H₂₁ClN₄O_(2[)372.852];(found) [M+H]⁺=373.

Example 52

With 4-(1,3-oxazol-5-yl)benzoic acid and Building block 0,(RS)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thionehydrochloride the(RS)—N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-oxazol-5-yl-benzamide(52) as a white solid. Mass (calculated) C₂₁H₁₉FN₄O_(2[)394.404];(found) [M+H]⁺=395.

Examples 53-59

In a reaction sequence analogous to that described in example 22 (methodB), the condensation of carboxylic acids with Building blocks H, K, andO followed by the treatment of the resulting thiones with a mixture ofammonia in water and tert-butyl hydroperoxide yielded the followingcompounds:

Example 53

With (RS)-2,2-difluoro-cyclopropanecarboxylic acid and Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the(RS)-2,2-difluoro-cyclopropanecarboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(53) as a white solid. Mass (calculated) C₁₅H₁₆F₃N₃O_(2[)327.304];(found) [M+H]⁺=328.

Example 54

With cyclopropanecarboxylic acid and Building block K,(R)-5-(5-amino-2-fluoro-phenyl)-5,6,6-trimethyl-morpholine-3-thione, thecyclopropanecarboxylic acid[3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(54) as a white foam. Mass (calculated) C₁₇H₂₂FN₃O_(2[)319.378]; (found)[M+H]⁺=320.

Example 55

With 1-(trifluoromethyl)cyclopropane-1-carboxylic acid and Buildingblock K,(R)-5-(5-amino-2-fluoro-phenyl)-5,6,6-trimethyl-morpholine-3-thione, the1-trifluoromethyl-cyclopropanecarboxylic acid[3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(55) as a white foam. Mass (calculated) C₁₈H₂₁F₄N₃O_(2[)387.375];(found) [M+H]⁺=388.

Example 56

With (RS)-2,2-difluoro-cyclopropanecarboxylic acid and Building block K,(R)-5-(5-amino-2-fluoro-phenyl)-5,6,6-trimethyl-morpholine-3-thione, the(RS)-2,2-difluoro-cyclopropanecarboxylic[3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(56) as a white foam. Mass (calculated) C₁₇H₂₀F₃N₃O_(2[)355.358];(found) [M+H]⁺=356.

Example 57

With 1-trifluoromethyl-cyclopropanecarboxylic acid and Building block 0,(RS)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thionehydrochloride the 1-trifluoromethyl-cyclopropanecarboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(57) as a white solid. Mass (calculated) C₁₆H₁₇F₄N₃O_(2[)359.321];(found) [M+H]⁺=360.

Example 58

With 3-chloro-cyclobutanecarboxylic acid and Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the3-chloro-cyclobutanecarboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(58) as a white solid. Mass (calculated) C₁₆H₁₉ClFN₃O_(2[)339.796];(found) [M+H]⁺=340.

Example 59

With 3,3-difluoro-cyclobutanecarboxylic acid and Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, the3,3-difluoro-cyclobutanecarboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(59) as a white solid. Mass (calculated) C₁₆H₁₈F₃N₃O_(2[)341.331];(found) [M+H]⁺=342.

Examples 60-66

In a reaction sequence analogous to that described in example 6 (methodB), starting from the condensation of a carboxylic acid with Buildingblock F, (RS)-5-(3-amino-phenyl)-5-methyl-morpholine-3-thione, followedby the treatment with ammonia in methanol as described in example 24b),the following compounds were obtained:

Example 60

With 5-cyclopropylmethoxy-pyridine-2-carboxylic acid the5-cyclopropylmethoxy-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride (60) (yield: 10% of theory). Mass (calculated)C₂₁H₂₄N₄O₃.ClH [416.906]; (found) [M+H]⁺=381.

The 5-cyclopropylmethoxy-pyridine-2-carboxylic acid was prepared asfollows:

a) 5-Cyclopropylmethoxy-pyridine-2-carboxylic acid methyl ester

A solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (2.0 g,13.1 mmol) in N,N-dimethylformamide was treated with potassium carbonate(2.71 g, 19.6 mmol) and 1-bromomethyl-cyclopropane (1.6 ml, 15.7 mmol).The reaction mixture was stirred at 100° C. for 16 hours. For theworkup, the reaction mixture was diluted with ethyl acetate, solidmaterial was filtered, and the filtrate evaporated at reduced pressure.The residue was purified by chromatography on silica using a gradient ofn-heptane and ethyl acetate=100/0 to 20/80 as the eluent to give the5-cyclopropylmethoxy-pyridine-2-carboxylic acid methyl ester as a yellowliquid (1.69 g, 62% of theory). Mass (calculated) C₁₁H₁₃NO_(3[)207.228];(found) [M+H]⁺=208.

b) 5-Cyclopropylmethoxy-pyridine-2-carboxylic acid

In a manner analogous to that described in example 48b) the hydrolysisof 5-cyclopropylmethoxy-pyridine-2-carboxylic acid methyl ester withlithium hydroxide yielded the title compound as a white solid. Mass(calculated) C₁₀H₁₁NO_(3 [)193.201]; (found) [M+H]⁺=194.

Example 61

With 5-(2-fluoro-ethoxy)-pyridine-2-carboxylic acid the5-(2-fluoro-ethoxy)-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride (61) (yield: 10% of theory). Mass (calculated)C₁₉H₂₁FN₄O₃.ClH [408.859]; (found) [M+H]⁺=373.

The 5-(2-fluoro-ethoxy)-pyridine-2-carboxylic acid was prepared in areaction sequence analogous to that in example 60 for the preparation ofthe 5-cyclopropylmethoxy-pyridine-2-carboxylic acid: Alkylation of the5-hydroxy-pyridine-2-carboxylic acid methyl ester with1-bromo-2-fluoroethane and hydrolysis of the5-(2-fluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester yielded the5-(2-fluoro-ethoxy)-pyridine-2-carboxylic acid as a white solid. Mass(calculated) C₈H₈FNO_(3[)185.153]; (found) [M+H]⁺=186.

Example 62

With 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid the5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride (62) (yield: 12% of theory). Mass (calculated)C₁₉H₂₀F₂N₄O₃.ClH [426.849]; (found) [M+H]⁺=391.

The 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid was prepared in areaction sequence analogous to that in example 60 for the preparation ofthe 5-cyclopropylmethoxy-pyridine-2-carboxylic acid: Alkylation of the5-hydroxy-pyridine-2-carboxylic acid methyl ester with 2,2-difluoroethyltriflate and hydrolysis of the5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester yieldedthe 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid as an off-whitesolid. Mass (calculated) C₈H₇F₂NO_(3[)203.143]; (found) [M+H]⁺=204.

Example 63

With pyrimidine-4-carboxylic acid the pyrimidine-4-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(63) (yield: 15% of theory). Mass (calculated) C₁₆H₁₇N₅O_(1[)311.343];(found) [M+H]⁺=312.

Example 64

With 5-but-3-enyloxy-pyridine-2-carboxylic acid the5-but-3-enyloxy-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(64) (yield: 10% of theory). Mass (calculated) C₂₁H₂₄N₄O_(3[)380.446];(found) [M+H]⁺=381.

The 5-but-3-enyloxy-pyridine-2-carboxylic acid was prepared in areaction sequence analogous to that in example 60 for the preparation ofthe 5-cyclopropylmethoxy-pyridine-2-carboxylic acid: Alkylation of the5-hydroxy-pyridine-2-carboxylic acid methyl ester with 4-bromo-1-buteneand hydrolysis of the 5-but-3-enyloxy-pyridine-2-carboxylic acid methylester yielded the 5-but-3-enyloxy-pyridine-2-carboxylic acid as a lightyellow solid. Mass (calculated) C₁₀H₁₁NO_(3[)193.201]; (found)[M+H]⁺=194.

Example 65

With 5-methyl-pyrazine-2-carboxylic acid the5-methyl-pyrazine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide(65) (yield: 17.5% of theory). Mass (calculated) C₁₇H₁₉N₅O_(2[)325.370];(found) [M+H]⁺=326.

Example 66

With 5-benzyloxy-pyridine-2-carboxylic acid (CAS74386-55-3) the5-benzyloxy-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride (66).

Example 67 (Method C) 3-Chloro-5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

a) 3-Chloro-5-cyano-pyridine-2-carboxylic acid[3-((R)-5-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

In a manner analogous to that described in example E1 (method E), thereaction of 3-chloro-5-cyano-pyridine-2-carboxylic acid with Buildingblock J,[(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine,using the 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride hydrate (DMTMM) as the condensating agent, yielded the titlecompound as a yellow solid (44% of theory). Mass (calculated)C₃₉H₃₃ClFN₅O_(4[)690.160]; (found) [M]⁺=690.

b) 3-Chloro-5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

A solution of 3-chloro-5-cyano-pyridine-2-carboxylic acid[3-((R)-5-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(80 mg, 0.12 mmol) in dichloromethane (2 ml) was treated at roomtemperature with trifluoroacetic acid (0.89 ml, 1.16 mmol); the yellowsolution immediately turned to orange. The reaction mixture was stirredat room temperature for 16 hours. For the workup, it was poured into asodium carbonate solution (1 M, 2 ml), then extracted withdichloromethane (10 ml). The organic layer was washed with brine (5 ml),dried over sodium sulfate, and evaporated. After chromatography onsilica gel using a gradient of dichloromethane and methanol=100/0 to93/7 the 3-chloro-5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidewas obtained. For further purification the product was dissolved indioxane and hydrochloric acid (4 N, 0.15 ml) was added. Afterevaporation at reduced pressure the salt was triturated in diethylether(2 ml), the solid material filtrated and dried. The title compound wasobtained as a white solid (5 mg, 10% of theory). Mass (calculated)C₁₈H₁₅ClFN₅O₂.ClH [424.260]; (found) [M+H]⁺=388.

Examples 68-72

In a manner analogous to that described in example E1 (method E), thereaction of carboxylic acids with Building blocks I and J, using the4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloridehydrate (DMTMM) as the condensating agent, followed by the cleavage ofthe [bis-(4-methoxy-phenyl)-phenyl-methyl]-(DMTr) amino protecting groupwith acid yielded the following compounds:

Example 68

With 5-chloro-3-fluoro-pyridine-2-carboxylic acid and Building block I,(RS)-[5-(3-amino-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine,the 5-chloro-3-fluoro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride (68) (yield: 45% of theory). Mass (calculated)C₁₇H₁₆ClFN₄O₂.ClH [399.251]; (found) [M+H]⁺=363.

Example 69

With 5-cyano-pyridine-2-carboxylic acid and Building block I,(RS)-[5-(3-amino-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine,the 5-cyano-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride (69) (yield: 5% of theory). Mass (calculated)C₁₈H₁₇N₅O₂.ClH [371.826]; (found) [M+H]⁺=363.

Example 70

With 5-chloro-3-ethyl-pyridine-2-carboxylic acid and Building block J,[(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine,the 5-chloro-3-ethyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride (70) as a white solid. Mass (calculated) C₁₉H₂₀ClFN₄O₂.ClH[427.305]; (found) [M+H]⁺=391.

The 5-chloro-3-ethyl-pyridine-2-carboxylic acid was prepared as follows:

In a three necked round bottom flask under a nitrogen atmosphere at −78°C., a solution of n-butyllithium in hexane (1.6 M, 7 ml, 11.1 mmol) wasadded dropwise to a solution of diisopropylamine (1.56 ml, 11.1 mmol) intetrahydrofuran (10 ml). The solution was stirred for 30 minutes, then asolution of 5-chloropyridine-2-carboxylic acid (800 mg, 5.0 mmol) intetrahydrofuran (50 ml) was added dropwise over 1 hour and the reactionwas stirred for 1 hour at −78° C. This solution was added dropwise viacannula to a solution of bromoethane (1.89 ml, 25.3 mmol) intetrahydrofuran (10 ml) at −30° C. The reaction mixture was stirredovernight at room temperature. For the workup, water (10 ml) was addedand the mixture was concentrated; hydrochloric acid (1 N) was added toreach pH 5 and the solution obtained was evaporated to dryness. Thesolid was solubilized in methanol and poured into acetonitrile. Thesolid formed was filtered off; the solution was collected andevaporated. The crude product was purified by chromatography to give the5-chloro-3-ethyl-pyridine-2-carboxylic acid (90 mg, 10% of theory) as awhite solid. Mass (calculated) C₈H₈ClNO_(2 [)185.611]; (found)[M+H]+=185, [M+2-H]⁺=187.

Example 71

With (RS)-3-sec-butyl-5-chloro-pyridine-2-carboxylic acid and Buildingblock J,[(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine,the 3-((RS)-sec-butyl)-5-chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride (71) as a white solid. Mass (calculated) C₂₁H₂₄ClFN₄O₂.ClH[455.358]; (found) [M+H]⁺=419.

The (RS)-3-sec-butyl-5-chloro-pyridine-2-carboxylic acid was prepared inanalogy to the preparation of 5-chloro-3-ethyl-pyridine-2-carboxylicacid by treatment of 5-chloropyridine-2-carboxylic acid with2-bromo-butane. The (RS)-3-sec-butyl-5-chloro-pyridine-2-carboxylic acidwas obtained as a white solid (yield: 6% of theory). Mass (calculated)C₁₀H₁₂ClNO_(2[)213.66]; (found) [M+H]⁺=213, [M+2-H]⁺=215.

Example 72

With 5-cyano-pyridine-2-carboxylic acid and Building block J,[(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine,the 5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride (72) (yield: 59% of theory). Mass (calculated)C₁₈H₁₆FN₅O₂.ClH [389.816]; (found) [M+H]⁺=354.

Example 73

With 5-difluoromethoxy-pyridine-2-carboxylic acid (CAS 117323-34-2) andBuilding block J,[(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine,the 5-difluoromethoxy-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride (73) (yield: 41% of theory). Mass (calculated)C₁₈H₁₇F₃N₄O₃.ClH [430.812]; (found) [M+H]⁺=395.

Example 74 5-Chloro-3-fluoro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

In analogy to example 22a) the reaction of5-chloro-3-fluoro-pyridine-2-carboxylic acid and Building block J,[(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine,using O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate as the condensating agent in presence of Huenig'sbase, followed by the cleavage of the[bis-(4-methoxy-phenyl)-phenyl-methyl]-(DMTr) amino protecting groupwith trifluoroacetic acid in dichloromethane yielded the title compound(yield: 24% of theory). Mass (calculated) C₁₇H₁₅ClF₂N₄O₂.ClH [417.241];(found) [M+H]⁺=381.

Example 75 5-Furan-2-yl-isoxazole-3-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

A solution of 5-furan-2-yl-isoxazole-3-carboxylic acid (CAS 98434-06-1)(77.3 mg, 0.42 mmol) in methanol (2 ml) was cooled to 0° C.4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloridehydrate (DMTMM) (135 mg, 0.46 mmol) was added and the mixture stirred at0° C. for 10 minutes. Thereafter, a solution of(RS)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(85 mg, 0.38 mmol) in methanol (1 ml) was added and the reaction mixturestirred at 0° C. for 2 hours, then kept at 4° C. for 16 hours. For theworkup, the reaction mixture was treated at 0° C. with sodium hydroxide(1 N, 6 ml). The yellow suspension was extracted with ethyl acetate (15ml), then the aqueous layer re-extracted with ethyl acetate (10 ml). Thecombined organic layers were dried over sodium sulfate and evaporated atreduced pressure. After chromatography on a Silicycle-Si-amine phaseusing a gradient of dichloromethane and methanol=100/0 to 90/10 the5-furan-2-yl-isoxazole-3-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidewas obtained as a white sold (16 mg, 11% of theory). Mass (calculated)C₁₉H₁₇FN₄O₄[384.365]; (found) [M+H]⁺=385.

Examples 76-78

In a manner analogous to that described in example E1 (method E), thecondensation of carboxylic acids with Building block P,(RS)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine,yielded the following compounds:

Example 76

With 5-furan-2-yl-pyridine-2-carboxylic acid (CAS 930110-99-9) the5-furan-2-yl-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(76) as a light yellow solid. Mass (calculated) C₂₁H₁₉FN₄O_(3[)394.404];(found) [M+H]⁺=395.

Example 77

With 5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (CAS 950603-19-7) the5-pyrrolidin-1-yl-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(77) as a white solid. Mass (calculated) C₂₁H₂₄FN₅O_(2[)397.452];(found) [M+H]⁺=398.

Example 78

With 5-thiophen-2-yl-isoxazole-3-carboxylic acid (CAS 763109-71-3) the5-thiophen-2-yl-isoxazole-3-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(78) as a white solid. Mass (calculated) C₂₁H₂₄FN₅O_(2[)397.452];(found) [M+H]⁺=398.

Example 79(RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-3,3,3-trifluoro-propionamide

In a manner analogous to that described in example E1 (method E), thecondensation of 3,3,3-trifluoro-propionic acid with Building block P,(RS)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine,yielded the title compound as a yellow oil. Mass (calculated)C₁₄H₁₅F₄N₃O_(2[)33.283]; (found) [M+H]⁺=334.

Examples 80-82

In a manner analogous to that described in example E1 (method E), thecondensation of carboxylic acids with Building block Q,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine,yielded the following compounds:

Example 80

With oxazole-2-carboxylic acid the oxazole-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(80) as a white solid. Mass (calculated) C₁₅H₁₅FN₄O_(3[)318.306];(found) [M+H]⁺=319.

Example 81

With 5-trifluoromethyl-pyrazine-2-carboxylic acid the5-trifluoromethyl-pyrazine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideformate (81) as a white solid. Mass (calculated)C₁₇H₁₅F₄N₅O₂.CH₂O_(2[)443.350]; (found) [M+H]⁺=398.

Example 82

With 5-trifluoromethyl-pyrimidine-2-carboxylic acid the5-trifluoromethyl-pyrazine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideformate (82) as a white solid. Mass (calculated)C₁₇H₁₅F₄N₅O₂.CH₂O_(2[)443.350]; (found) [M+H]⁺=398.

Examples 83-97

In a manner analogous to that described in example E1 (method E), thecondensation of carboxylic acids with Building block Q,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine,yielded the compounds below. These compounds were purified bypreparative HPLC using a gradient of water and methanol (plus 0.05%formic acid)=95/5 to 0/100 as the eluent.

Example 83

With 2,2,3,3-tetrafluoro-propionic acid theN-[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2,2,3,3-tetrafluoro-propionamideformate (83) as a colorless amorphous material. Mass (calculated)C₁₄H₁₄F₅N₃O₂.CH₂O_(2[)397.300]; (found) [M+H]⁺=352.

Example 84

With methoxy-acetic acid theN-[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2-methoxy-acetamideformate (84) as a white amorphous material. Mass (calculated)C₁₄H₁₈FN₃O₃.CH₂O_(2[)341.330]; (found) [M+H]⁺=296.

Example 85

With(RS)-3,3,3-trifluoro-2-[(RS)-1-(tetrahydro-furan-2-yl)methyl]-propionicacid the(RS)—N-[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-3,3,3-trifluoro-2-[(RS)-1-(tetrahydro-furan-2-yl)methyl]-propionamideformate (85) as a white amorphous material. Mass (calculated)C₁₉H₂₃F₄N₃O₃.CH₂O_(2[)463.420]; (found) [M+H]⁺=418.

Example 86

With 1-methoxymethyl-cyclopropanecarboxylic acid the1-methoxymethyl-cyclopropanecarboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideformate (86) as a white amorphous material. Mass (calculated)C₁₇H₂₂FN₃O₃.CH₂O_(2[)381.400]; (found) [M+H]⁺=336.

Example 87

With (RS)-2-fluoro-propionic acid the(RS)—N-[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2-fluoro-propionamideformate (87) as a white amorphous material. Mass (calculated)C₁₄H₁₇F₂N₃O₂.CH₂O_(2 [)343.328]; (found) [M+H]⁺=298.

Example 88

With isobutyric acid theN-[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-isobutyramideformate (88) as a white amorphous material. Mass (calculated)C₁₅H₂₀FN₃O₂.CH₂O_(2[)339.360]; (found) [M+H]⁺=294.

Example 89

With (RS)-2,3,3,3-tetrafluoro-propionic acid the(RS)—N-[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2-fluoro-propionamideformate (89) as a white amorphous material. Mass (calculated)C₁₄H₁₄F₅N₃O₂.CH₂O_(2 [)397.298]; (found) [M+H]⁺=352.

Example 90

With 2,2-difluoro-propionic acid theN-[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2,2-difluoro-propionamideformate (90) as a white amorphous material. Mass (calculated)C₁₄H₁₆F₃N₃O₂.CH₂O_(2[)361.320]; (found) [M+H]⁺=316.

Example 91

With difluoro-acetic acid theN-[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2,2-difluoro-acetamideformate (91) as a white foam. Mass (calculated)C₁₃H₁₄F₃N₃O₂.CH₂O_(2[)347.290]; (found) [M+H]⁺=302.

Example 92

With 2-fluoro-2-methyl-propionic acid theN-[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-2-fluoro-2-methyl-propionamideformate (92) as a white amorphous material. Mass (calculated)C₁₅H₁₉F₂N₃O₂.CH₂O_(2[)357.350]; (found) [M+H]⁺=312.

Example 93

With acetic acid theN-[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-acetamideformate (93) as a white amorphous material. Mass (calculated)C₁₃H₁₆FN₃O₂.CH₂O_(2[)311.310]; (found) [M+H]⁺=266.

Example 94

With propionic acid theN-[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-propionamideformate (94) as a white amorphous material. Mass (calculated)C₁₄H₁₈FN₃O₂.CH₂O_(2[)325.340]; (found) [M+H]⁺=280.

Example 95

With 3-methyl-butyric acid theN-[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-3-methyl-butyramideformate (95) as a white amorphous material. Mass (calculated)C₁₆H₂₂FN₃O₂.CH₂O_(2[)353.390]; (found) [M+H]⁺=308.

Example 96

With (RS)-tetrahydro-furan-3-carboxylic acid the(RS)-tetrahydro-furan-3-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideformate (96) as a white amorphous material. Mass (calculated)C₁₆H₂₀FN₃O₃.CH₂O_(2[)367.375]; (found) [M+H]⁺=322.

Example 97

With formic acid theN-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-formamideformate (97) as a white amorphous material. Mass (calculated)C₁₂H₁₄FN₃O₂.CH₂O_(2[)297.280]; (found) [M+H]⁺=252.

Examples 98-99 (Method F)

In a manner analogous to that described in example E1 (method E), thereaction of carboxylic acids with Building block H,(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione, using the4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloridehydrate (DMTMM) as the condensating agent, followed by the treatment ofthe resulting thiones with a mixture of ammonia in water and tert-butylhydroperoxide as described in example 22, yielded the followingcompounds:

Example 98

With 5-chloro-3-methyl-pyridine-2-carboxylic acid the5-chloro-3-methyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(98) as a white foam. Mass (calculated) C₁₈H₁₈ClFN₄O_(2[)376.817];(found) [M+H]⁺=377.

Example 99

With 5-fluoro-pyridine-2-carboxylic acid the5-fluoro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(99) as a white foam. Mass (calculated) C₁₇H₁₆F₂N₄O_(2[)346.335];(found) [M+H]⁺=347.

1. A compound of formula I,

wherein X is O or S, R¹ is selected from the group consisting of i)lower alkyl, ii) lower alkyl substituted by 1-5 substituentsindividually selected from cycloalkyl, halogen, halogen-lower alkoxy andlower alkoxy, and iii) cycloalkyl, R² is selected from the groupconsisting of i) aryl, ii) aryl substituted by 1-4 substituentsindividually selected from cyano, cyano-lower alkyl, halogen,halogen-lower alkoxy, halogen-lower alkyl, heteroaryl, lower alkoxy,lower alkoxy-lower alkyl and lower alkyl, iii) cycloalkyl, iv)cycloalkyl substituted by 1-4 substituents individually selected fromcyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-loweralkyl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, v)heteroaryl, vi) heteroaryl substituted by 1-4 substituents individuallyselected from aryl, cyano, cyano-lower alkyl, halogen, halogen-loweralkoxy, halogen-lower alkyl, cycloalkyl-lower alkoxy, loweralkenyl-lower alkoxy, aryl-lower alkoxy, heteroaryl, heterocyclyl, loweralkoxy, lower alkoxy-lower alkyl and lower alkyl, vii) heterocyclyl, andviii) heterocyclyl substituted by 1-4 substituents individually selectedfrom amino, cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy,halogen-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl and loweralkyl, R³ is individually selected from the group consisting of i)halogen and ii) lower alkyl, R⁴ is individually selected from the groupconsisting of i) H and ii) lower alkyl, R⁵ is individually selected fromthe group consisting of i) H and ii) lower alkyl, R⁶ is individuallyselected from the group consisting of i) H and ii) lower alkyl, R⁷ isindividually selected from the group consisting of i) H, ii) aryl, andiii) lower alkyl, and n is 0, 1 or 2, or a pharmaceutically acceptablesalt thereof.
 2. The compound of claim 1, wherein X is O or S, R¹ isselected from the group consisting of i) lower alky, and ii) cycloalkyl,R² is selected from the group consisting of i) aryl substituted by 1-4substituents individually selected from cyano, halogen and heteroaryl,ii) cycloalkyl, iii) cycloalkyl substituted by 1-4 substituentsindividually selected from halogen, halogen-lower alkyl, loweralkoxy-lower alkyl and lower alkyl, iv) heteroaryl, v) heteroarylsubstituted by 1-4 substituents individually selected from aryl, cyano,halogen, halogen-lower alkoxy, halogen-lower alkyl, cycloalkyl-loweralkoxy, lower alkenyl-lower alkoxy, aryl-lower alkoxy, heteroaryl,heterocyclyl, and lower alkyl, and vi) heterocyclyl, R³ is halogen, R⁴is H or lower alkyl, R⁵ is H or lower alkyl, R⁶ is H or lower alkyl, R⁷is H, aryl or lower alkyl, and n is 0 or 1 or a pharmaceuticallyacceptable salt thereof.
 3. The compound of claim 1, having formula Ix

wherein X is O or S, R¹ is selected from the group consisting of i)lower alkyl, ii) lower alkyl substituted by 1-5 substituentsindividually selected from cycloalkyl, halogen, halogen-lower alkoxy andlower alkoxy, and iii) cycloalkyl, R² is selected from the groupconsisting of i) aryl, ii) aryl substituted by 1-4 substituentsindividually selected from cyano, cyano-lower alkyl, halogen,halogen-lower alkoxy, halogen-lower alkyl, lower alkoxy, loweralkoxy-lower alkyl and lower alkyl, iii) cycloalkyl, iv) cycloalkylsubstituted by 1-4 substituents individually selected from cyano,cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-lower alkyl,lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, v) heteroaryl,vi) heteroaryl substituted by 1-4 substituents individually selectedfrom cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy,halogen-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl and loweralkyl, vii) heterocyclyl, and viii) heterocyclyl, substituted by 1-4substituents individually selected from cyano, cyano-lower alkyl,halogen, halogen-lower alkoxy, halogen-lower alkyl, lower alkoxy, loweralkoxy-lower alkyl and lower alkyl, R³ is individually selected from thegroup consisting of i) halogen and ii) lower alkyl, n is 0, 1 or 2, or apharmaceutically acceptable salt thereof.
 4. The compound of claim 1,wherein X is O.
 5. The compound of claim 1, wherein R¹ is lower alkyl orcycloalkyl.
 6. The compound of claim 5, wherein R¹ is methyl orcyclopropyl.
 7. The compound of claim 1, wherein R² is selected from thegroup consisting of i) aryl substituted by 1-4 substituents individuallyselected from cyano, halogen and heteroaryl, ii) cycloalkyl, iii)cycloalkyl substituted by 1-4 substituents individually selected fromhalogen, halogen-lower alkyl and lower alkoxy-lower alkyl, iv)heteroaryl, v) heteroaryl substituted by 1-4 substituents individuallyselected from aryl, cyano, halogen, halogen-lower alkoxy, halogen-loweralkyl, cycloalkyl-lower alkoxy, lower alkenyl-lower alkoxy, aryl-loweralkoxy, heteroaryl, heterocyclyl, and lower alkyl, and vi) heterocyclyl.8. The compound of claim 1, wherein R² is aryl substituted by 1-4halogens, heteroaryl or heteroaryl substituted by 1-4 substituentsindividually selected from halogen, halogen-lower alkoxy, halogen-loweralkyl and lower alkyl.
 9. The compound of claim 7, wherein R² isheteroaryl substituted by 1-4 substituents individually selected fromhalogen, halogen-lower alkoxy, halogen-lower alkyl and lower alkyl. 10.The compound of claim 1, wherein R² is1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl;1,1-difluoromethyl-1H-pyrazole-3-yl; 1-methoxymethyl-cycloprop-1-yl;1-methyl-1H-indazol-3-yl; 1-trifluoromethyl-cycloprop-1-yl;2,2-difluoro-cycloprop-1-yl; 2,4-dichloro-phenyl; 2,5-difluoro-phenyl;2,5-dimethyl-fur-3-yl; 2,5-dimethyl-oxazol-4-yl;2,5-dimethyl-thien-3-yl; 2-methyl-4-trifluoromethyl-thiazole-5-yl;2-methyl-oxazol-4-yl; 2-methyl-thiazol-4-yl;3-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl;3,3,3-trifluoro-1-(tetrahydro-furan-2-yl)-propyl;3,3-difluoro-cyclobut-1-yl; 3,5-dichloro-pyridin-2-yl;3,5-difluoro-pyridin-2-yl; 3-chloro-5-cyano-pyridin-2-yl;3-chloro-5-trifluoromethyl-pyridin-2-yl; 3-chloro-cyclobut-1-yl;3-chloro-phenyl; 3-chloro-thiophen-2-yl; 3-fluoro-pyridin-2-yl;3-methyl-thiophen-2-yl; 3-sec-butyl-5-chloro-pyridin-2-yl;4-chloro-1-methyl-1H-pyrazole-3-yl; 4-chloro-2-fluoro-phenyl;4-chloro-2-iodo-phenyl; 4-chloro-phenyl; 4-cyano-2-fluoro-phenyl;4-oxazol-5-yl-phenyl; 5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl;5-(2,2-difluoro-ethoxy)-pyridin-2-yl; 5-(2-fluoro-ethoxy)-pyridin-2-yl;5-benzyloxy-pyridin-2-yl; 5-but-3-enyloxy-pyridin-2-yl;5-butyl-pyridin-2-yl; 5-chloro-3-ethyl-pyridin-2-yl;5-chloro-3-fluoro-pyridin-2-yl; 5-chloro-3-methyl-pyridin-2-yl;5-chloro-pyridin-2-yl; 5-chloro-pyrimidin-2-yl; 5-chloro-thien-2-yl;5-cyano-pyridin-2-yl; 5-cyclopropylmethoxy-pyridin-2-yl;5-difluoromethoxy-pyridin-2-yl; 5-fluoro-pyridin-2-yl;5-furan-2-yl-isoxazol-3-yl; 5-furan-2-yl-pyridin-2-yl;5-methyl-pyrazin-2-yl; 5-phenyl-oxazol-4-yl;5-pyrrolidin-1-yl-pyridin-2-yl; 5-thiophen-2-yl-isoxazol-3-yl;5-trifluoromethyl-pyrazin-2-yl; 5-trifluoromethyl-pyrimidin-2-yl;cyclopropyl; oxazole-2-yl; pyrazin-2-yl; pyrazolo[1,5-a]pyridin-2-yl;pyrimidin-4-yl or tetrahydro-furan-3-yl.
 11. The compound of claim 10,wherein R² is 1-methyl-1H-indazol-3-yl; 2-methyl-oxazol-4-yl;2-methyl-thiazol-4-yl; 3-chloro-phenyl; 4-chloro-2-fluoro-phenyl;4-chloro-2-iodo-phenyl; 4-chloro-phenyl; 5-chloro-pyridin-2-yl;5-chloro-thien-2-yl; 1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl;5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl; pyrazin-2-yl,pyrazolo[1,5-a]pyridin-2-yl; 2,4-dichloro-phenyl; 2,5-difluoro-phenyl;2,5-dimethyl-fur-3-yl; 2,5-dimethyl-oxazol-4-yl;2,5-dimethyl-thien-3-yl; 3,5-dichloro-pyridin-2-yl or3,5-difluoro-pyridin-2-yl.
 12. The compound of claim 11, wherein R² is5-chloro-pyridin-2-yl; 3,5-dichloro-pyridin-2-yl;1,1-difluoromethyl-1H-pyrazole-3-yl; 3,5-difluoro-pyridin-2-yl;5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl; 3-chloro-5-cyano-pyridin-2-yl;5-cyano-pyridin-2-yl; 5-difluoromethoxy-pyridin-2-yl or5-chloro-3-fluoro-pyridin-2-yl.
 13. The compound of claim 1, wherein R²is 5-chloro-pyridin-2-yl.
 14. The compound of claim 1, wherein n is 1.15. The compound of claim 1, wherein R³ is halogen.
 16. The compound ofclaim 15, wherein R³ is F.
 17. The compound of claim 1, wherein n is 0.18. The compound of claim 1, selected from the group consisting of3,5-Difluoro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,3,5-Dichloro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,(RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-chloro-2-fluoro-benzamide,(RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,4-dichloro-benzamide,(RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,5-difluoro-benzamide,(RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-3-chloro-benzamide,5-Chloro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,5-Chloro-thiophene-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,2,5-Dimethyl-thiophene-3-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,and 2-Methyl-thiazole-4-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amideor a pharmaceutically acceptable salt thereof.
 19. The compound of claim1, selected from the group consisting of2,5-Dimethyl-oxazole-4-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,2-Methyl-oxazole-4-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,2,5-Dimethyl-furan-3-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,1-(2,2,2-Trifluoro-ethyl)-1H-pyrazole-3-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,1-Methyl-1H-indazole-3-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,Pyrazolo[1,5-a]pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,(RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-chloro-2-iodo-benzamide,5-Chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,(RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-benzamide,and 5-Chloro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideor a pharmaceutically acceptable salt thereof.
 20. The compound of claim1, selected from the group consisting of 5-Chloro-pyridine-2-carboxylicacid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-Chloro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,Pyrazine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,(RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-thiobenzamide,5-Chloro-pyridine-2-carboxylic acid [3-((3R,6R) and(3S,6S)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-Chloro-pyridine-2-carboxylic acid [3-((3R,6S)— and(3S,6R)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-Chloro-pyridine-2-carboxylic acid[3-((3R,6R)-5-amino-3-methyl-6-phenyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,and 5-Chloro-pyridine-2-carboxylic acid[3-((3R,6S)-5-amino-3-methyl-6-phenyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideor a pharmaceutically acceptable salt thereof.
 21. The compound of claim1, selected from the group consisting of 5-Butyl-pyridine-2-carboxylicacid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,3,5-Dichloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Chloro-pyrimidine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-Trifluoromethyl-furan-3-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,3-Fluoro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,2-Methyl-oxazole-4-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,1-Difluoromethyl-1H-pyrazole-3-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,and 3,5-Difluoro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideor a pharmaceutically acceptable salt thereof.
 22. The compound of claim1, selected from the group consisting ofN-[3-((R)-5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-cyano-2-fluoro-benzamide,4-Chloro-1-methyl-1H-pyrazole-3-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,3-Methyl-thiophene-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-Phenyl-oxazole-4-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,3-Chloro-thiophene-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,2-Methyl-4-trifluoromethyl-thiazole-5-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,3-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,and 5-Chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3,6,6-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amideor a pharmaceutically acceptable salt thereof.
 23. The compound of claim1, selected from the group consisting of(RS)—N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-oxazol-5-yl-benzamide,(RS)-2,2-Difluoro-cyclopropanecarboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,Cyclopropanecarboxylic acid[3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,1-Trifluoromethyl-cyclopropanecarboxylic acid[3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,(RS)-2,2-Difluoro-cyclopropanecarboxylic acid[3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,1-Trifluoromethyl-cyclopropanecarboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,3-Chloro-cyclobutanecarboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,3,3-Difluoro-cyclobutanecarboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Cyclopropylmethoxy-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,and 5-(2-Fluoro-ethoxy)-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amideor a pharmaceutically acceptable salt thereof.
 24. The compound of claim1, selected from the group consisting of5-(2,2-Difluoro-ethoxy)-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,Pyrimidine-4-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,5-But-3-enyloxy-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,5-Methyl-pyrazine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,5-Benzyloxy-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,3-Chloro-5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-Chloro-3-fluoro-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,5-Cyano-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Chloro-3-ethyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,and 3(RS)-sec-Butyl-5-chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideor a pharmaceutically acceptable salt thereof.
 25. The compound of claim1, selected from the group consisting of 5-Cyano-pyridine-2-carboxylicacid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-Difluoromethoxy-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Chloro-3-fluoro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Furan-2-yl-isoxazole-3-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Furan-2-yl-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Pyrrolidin-1-yl-pyridine-2-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Thiophen-2-yl-isoxazole-3-carboxylic acid[3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,Oxazole-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Trifluoromethyl-pyrazine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,and 5-Trifluoromethyl-pyrimidine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideor a pharmaceutically acceptable salt thereof.
 26. The compound of claim1, selected from the group consisting of1-Methoxymethyl-cyclopropanecarboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,(RS)-Tetrahydro-furan-3-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Chloro-3-methyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Fluoro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Chloro-pyridine-2-carboxylic acid[3-(5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Chloro-pyridine-2-carboxylic acid [3-((3R,6R) and(3S,6S)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Chloro-pyridine-2-carboxylic acid [3-((3R,6S)— and(3S,6R)-5-amino-6-benzyl-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,3,5-Dichloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,and 1-Difluoromethyl-1H-pyrazole-3-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,or a pharmaceutically acceptable salt thereof.
 27. The compound of claim1, selected from the group consisting of1-Difluoromethyl-1H-pyrazole-3-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-Chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-((R)-5-amino-2,2,3-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-Chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3,6,6-trimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,3-Chloro-5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-Cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Difluoromethoxy-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-Chloro-3-fluoro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,1-(2,2,2-Trifluoro-ethyl)-1H-pyrazole-3-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,and 1-Methyl-1H-indazole-3-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide or apharmaceutically acceptable salt thereof.
 28. The compound of claim 1,selected from the group consisting of 2,5-Dimethyl-furan-3-carboxylicacid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,2,5-Dimethyl-oxazole-4-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,2,5-Dimethyl-thiophene-3-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,2-Methyl-oxazole-4-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,2-Methyl-thiazole-4-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,3,5-Dichloro-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,3,5-Difluoro-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-(5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,and 5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride or a pharmaceutically acceptable salt thereof.
 29. Thecompound of claim 1 selected from the group consisting of5-Chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,5-Chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Chloro-pyridine-2-carboxylic acid[3-(5-amino-3-cyclopropyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,5-Chloro-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,5-Chloro-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,5-Chloro-thiophene-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl-]-amide,N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-thiobenzamide,N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-chloro-2-fluoro-benzamide,N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,4-dichloro-benzamide,andN-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-2,5-difluoro-benzamideor a pharmaceutically acceptable salt thereof.
 30. The compound of claim1 selected from the group consisting ofN-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-3-chloro-benzamide,N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-chloro-2-iodo-benzamide,N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-benzamide,Pyrazine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride, Pyrazolo[1,5-a]pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide,5-Chloro-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl-]-amide,and 5-Chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideor a pharmaceutically acceptable salt thereof.
 31. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula I

wherein X is O or S, R¹ is selected from the group consisting of i)lower alkyl, ii) lower alkyl substituted by 1-5 substituentsindividually selected from cycloalkyl, halogen, halogen-lower alkoxy andlower alkoxy, and iii) cycloalkyl, R² is selected from the groupconsisting of i) aryl, ii) aryl substituted by 1-4 substituentsindividually selected from cyano, cyano-lower alkyl, halogen,halogen-lower alkoxy, halogen-lower alkyl, heteroaryl, lower alkoxy,lower alkoxy-lower alkyl and lower alkyl, iii) cycloalkyl, iv)cycloalkyl substituted by 1-4 substituents individually selected fromcyano, cyano-lower alkyl, halogen, halogen-lower alkoxy, halogen-loweralkyl, lower alkoxy, lower alkoxy-lower alkyl and lower alkyl, v)heteroaryl, vi) heteroaryl substituted by 1-4 substituents individuallyselected from aryl, cyano, cyano-lower alkyl, halogen, halogen-loweralkoxy, halogen-lower alkyl, cycloalkyl-lower alkoxy, loweralkenyl-lower alkoxy, aryl-lower alkoxy, heteroaryl, heterocyclyl, loweralkoxy, lower alkoxy-lower alkyl and lower alkyl, vii) heterocyclyl, andviii) heterocyclyl substituted by 1-4 substituents individually selectedfrom amino, cyano, cyano-lower alkyl, halogen, halogen-lower alkoxy,halogen-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl and loweralkyl, R³ is individually selected from the group consisting of i)halogen and ii) lower alkyl, R⁴ is individually selected from the groupconsisting of i) H and ii) lower alkyl, R⁵ is individually selected fromthe group consisting of i) H and ii) lower alkyl, R⁶ is individuallyselected from the group consisting of i) H and ii) lower alkyl, R⁷ isindividually selected from the group consisting of i) H, ii) aryl, andiii) lower alkyl, and n is 0, 1 or 2, or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier.